FI79528C - Process for the preparation of pharmaceutically active 2-oxoazetidine derivatives - Google Patents

Abstract

1-Sulfo-2-oxoazetidine derivatives of the general formula (I) <CHEM> wherein R1 is amino group which may optionally be acyiated or protected, X is hydrogen or methoxy, and R4 is azido, a halogen, amino group which may optionally be acylated or a group of the formula -OR5, <CHEM> or -S-S-R5 in which R5 is an organic residue and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof, or an ester thereof as well as methods of production in accordance with the following schemes: <CHEM> wherein R2 is an acylated or protected amino group, R3 is an acylated amino group, and R1 and R4 are as above defined. The compounds [I] have antimicrobial and beta -lactamase inhibitory activity.

Description

1 79528

Process for the preparation of pharmaceutically active 2-oxoazetidine derivatives Förfarande för framställning av farmaceutiskt verksamma 2-oxoazetidine derivatives

The present invention relates to a process for the preparation of novel 1-sulfo-3,4-substituted-2-oxoazetidine derivatives having antimicrobial or β-lactamase inhibitory activity.

In recent years, various 2-oxo-azetidine derivatives have been synthetically prepared. According to a known method, a vinyl ester and a chlorosulfonyl isocyanate are reacted to give a 4-acetoxy-2-oxoazetidine compound, which is then subjected to a nucleophilic substitution reaction to attach a benzoyloxy, alkylthio, benzylthio or other group to the 4-position of this compound (Annalen der Chemie 1974). 539). ' It appears that in this process a compound having a chlorosulfonyl group in the 1-position is formed, but since this chlorosulfonyl group tends to cleave off, this intermediate cannot be easily isolated.

In researching new and useful azetidine derivatives, the inventors have found that azetidine derivatives having a sulfo group in the 1-position are suitable for the above purpose and have continued their research. The present invention is based on the development of the above finding and studies.

The invention therefore relates to a process for the preparation of a pharmaceutically active 1-sulfo-2-oxoacetidine compound of the following formula -JU-I (I)

J— N-SO3H

or wherein 2 79528 X is hydrogen or methoxy;

R 1 is (1) amino, (2) acylated amino, wherein the acyl group is (A) a group of the formula R 6 -CO- wherein R 9 is a 5- or 6-membered heterocyclic group containing one or two nitrogen atoms and optionally one oxygen atom, such as isoxazolyl, piperazinyl, imidazolinyl, etc., and which may be substituted by (a) lower alkyl or (b) phenyl optionally substituted by halogen; (B) a group of formula

R7-NH-CH-CO- 'I

Rg wherein R7 is (i) a group of the formula Rg-CO-, wherein Rg is a 5- or 6-membered heterocyclic group having 2 to 4 nitrogen atoms, such as pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolinyl, imidazolidinyl, tetrazolyl, triazinyl, etc., which may be substituted with (a) C 1 -C 12 alkyl, (b) oxo, (c) 3-thiophenaldoimino, or (d) sulfo, or (ii) a group of formula is

Rs' ^ N-CO- /

Re "3 79528 wherein R 5" and R 5 "'are independently (a) hydrogen, (b) lower alkyl, (c) lower alkylcarbamoyl, or (d) sulfo,

Rg is (i) lower alkyl which may be substituted by hydroxyl, formyloxy or halogen, (ii) phenyl, (iii) a 5-membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, such as thienyl, furyl, pyrrolyl, etc. ., and which may be substituted by amino, (iv) 2-propynyl or '(v) benzothienyl,: V: (C) a group of formula

Rio-C-CO-I-NO-R13 wherein R12 is (i) a 5-membered heterocyclic group containing one nitrogen, sulfur or oxygen atom, optionally having one nitrogen atom, such as 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, etc., and which may be substituted (a) amino, (b) C 2 -C 4 acylamino which may be substituted by halogen, or

• I

(ii) 2- (sulfoamino, formylamino, methylthioacetamido or tritylamino) thiazol-4-yl,

R 13 is (i) lower alkyl or (ii) a group of the formula -R 14 -R 15 where R 14 is lower alkylene and R 15 is carboxyl, a conventional ester of carboxyl such as methyl, ethyl, propyl, t-butyl li-, p-nitrobenzyl, 2-trimethylsilylethyl, t-butyldiphenylsilyl, diphenylmethyl ester, or a 5-membered 4,79528 heterocyclic group containing 3 to 4 nitrogen atoms, (D) a group of the formula CH-CO-

R 17 wherein R 17 is halogen, (E) a group of the formula R 19 -CH 2 -CO- wherein R 19 is (i) phenyl, (ii) phenoxy or (iii) 5- or 6-membered, single sulfur atom or 2 ... A heterocyclic group containing 4 nitrogen atoms such as 2-thienyl, 3-thienyl, 1-tetrazolyl, 5-tetrazolyl, imidazolyl / etc .; (3) an amino group protected by an amino-protecting group used in the field of β-lactam and peptide syntheses; (4) 2 - ((2- (tritylamino or amino) thiazol-4-yl) carboxymethyliminooxy) -2-methylpropionamide; R 4 is (1) azido, (2) halogen, (3) an amino group which may be acylated, the acyl moiety being lower alkylcarbonyl, (79) a group of the following formulas -OR 5; -S (O) n R 5, or -SS-R 5 where R 5 is (A) a C 1 -C 10 hydrocarbon which may be substituted by (1) lower alkoxycarbonyl or (2) amino which may be acylated, the acyl moiety being formyl, acetyl or p-nitrobenzyloxycarbonyl, (B) a carbonyl group substituted with a C 1 -C 10 hydrocarbon which may be substituted by phenyl, f (C) tetrazolyl which may be substituted by lower alkyl, or (D) benzothiazolyl; and 'n is 0, 1 or 2; or (5) n-propylthio-thiocarbonylthio; or a pharmaceutically acceptable salt or ester thereof.

The process according to the invention is characterized in that a) a compound of the following formula (II)

X

Wherein R 2 is an acylated or protected amino group as defined for R 1 and X and R 4 have the same meaning as defined above, or a salt or silyl derivative thereof 6 79528 is sulfonated, after which the protecting group is necessary. in the case where R 2 is a protected amino group as defined in connection with R 1, or b) for the preparation of a compound of formula (I) wherein R 1 is an acylated amino group and X and R 4 are as defined above, are removed according to the following formula (III) compound χ R4 NH2 - / j-N (111>

0 ^ SOjH

wherein X and R 4 are as defined above, or a salt or silyl derivative thereof is acylated, and if desired, the compound thus obtained is converted into a pharmaceutically acceptable salt or ester thereof.

The compounds of the invention may be used in antimicrobial compositions comprising a compound of formula (I) and in β-lactamase inhibiting compositions containing a compound of formula (I).

Novel compounds of the invention to be prepared according to the invention are known from SE patent publication 433,229, which is directed to 1-sulfo-2-oxoazetidine compounds. However, these known compounds have no substituent at all in the 4-position, whereas the new compounds (I) have a specific substituent in the 4-position.

In the above formulas, the halogen represented by the group R4 is fluorine, chlorine, bromine or iodine. The hydrocarbon group represented by R5 is an aliphatic group which may be straight-chain, branched or cyclic and may contain a double bond or a triple bond, or an aromatic group such as phenyl, naphthyl, etc. The acyl group represented by R5 is a carbonyl group which may be substituted by such hydrocarbon group.

These hydrocarbon groups, acyl groups and heterocyclic groups may each have a substituent lower (O 3 -3) alkoxy, lower alkoxycarbonyl, carboxyl, halogen (e.g. fluorine, chlorine, bromine), phenoxy, phenyl, a heterocyclic group (e.g. furyl, thienyl, tetrazolyl, thiazolyl), lower (C 1-3) alkylthio (e.g. methylthio, ethylthio), heterocyclic thio (e.g. tetrazolylthio, thiadiazolylthio), amino which may be acylated or substituted with iminomethyl or carbamoyl. , cyano, etc. The acyl moieties of these: **: optionally acylated amino groups are; preferably formyl, acetyl, propionyl, etc.

In the above formulas, the acyl moiety of the optionally acylated "amino" group represented by the symbol R 4 may be, for example, a carbonyl group substituted with lower (C 1-4) alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, tert Substituent for this carbonyl group may be O1a amino, halogen (e.g. chlorine, bromine, fluorine), hydroxyl, lower (C1-4) alkyl, lower (C1-4) alkoxy, optionally esterified carboxyl.

With further reference to the above formulas, note that the acyl moiety of the acylated amino group R 1, R 2 or R 3 may be an acyl group associated with the 6-amino i: of known penicillin derivatives or an acyl group associated with the 7-amino of known cephalosporin derivatives.

Examples of the heterocyclic group Rg include pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolinyl, imidazolidinyl, pyrido (2,3-d) pyrimidinyl, tetrazolyl, triazinyl, and the like.

8 79528

The lower alkyl portion of the lower alkyl group Rg preferably has 1 to 3 carbon atoms, and the substituents may be a precursor. hydroxyl, formyloxy, phenyl, carbamoyl, methylcarbamoyl, methylthio, thienylacetamido, ethoxycarbonylmethylcarbamoyl, N-methyltetrazolylthio, halogen, sulfamoyl, etc.

Examples of the optionally substituted heterocyclic group R12 are 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl and 3-pyrrolyl. Substituents for these heterocyclic groups include e.g. lower (C 1-3) alkyl, lower (C 1-3) alkoxy, hydroxyl, mesyl, halogen, *: imino, amino, mesylamino or (C 2-4) acylamino which may * be substituted by halogen.

The lower alkyl portion of the lower alkyl group R13 preferably has 1 to 3 carbon atoms. Optionally substituted lower. alkyl R13 substituents include carbamoyl, * halogen, etc.

In the lower alkylene of the formula -R14-R15, R14 (or R13) preferably has 1 to 3 carbon atoms and this alkylene is e.g.

: methylene, ethylene, dimethylmethylene, methylethylene or ethyl: methylene.

Examples of the carboxylated ester group R15 are methyl, ethyl, propyl, t-butyl, p-nitrobenzyl, 2-trimethylsilylethyl and t-butyldiphenylsilyl and diphenylmethyl esters.

Examples of the 5-membered heterocyclic group of the heterocyclic group R15 are tetrazolyl and triazolyl.

Substituents for the optionally substituted phenyl group R jg may be, for example, lower (C 1-3) alkyl, lower (C 1-3) alkoxy, halogen, nitro, amino, hydroxyl or substituted aminomethyl. Substituents for this substituted aminomethyl group may include e.g. carbamoyl, (2-oxo-3-benzylideneaminoimidazolidin-1-yl) carbonyl and (2-oxo-imidazolidin-1-yl) carbonyl.

Substituents for the optionally substituted phenoxy group R 1g may be, for example, lower (C 1-3) alkyl, lower (C 1-3) alkoxy, halogen, nitro, amino, hydroxyl or aminomethyl. The substituents are the same as mentioned above as substituents of the optionally substituted phenyl group R 1g.

Examples of the heterocyclic group R19 are 2-thienyl, benzothienyl, 3-thienyl, 2-pyridyl, 3-pyridyl-4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, [[: isothiazolyl, 1-tetrazolyl, 5-tetrazolyl, pyrrolidinyl, imidazolyl, etc.

• a • k

Substituents for the heterocyclic group R 9g may be, for example, lower (C 1-3) alkyl, lower (C 1-3) alkoxy, halogen, nitro, hydroxyl, optionally protected amino, carboxyl, oxo, (C 2-4) acylamino, which may be substituted with halogen, or (C2-4) acyl.

In the context of the terms used above in connection with acyl groups or moieties, -alkyl is e.g. methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, iso- • * * 1, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, 3- heptyl, octyl, no-J) phenyl, decyl, undecyl, dodecyl and cyclohexyl Lower (C 1-8) alkyls include methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, and lower (C 1-3) alkyls include methyl, trifluoromethyl, ethyl, n-propyl and isopropyl. alkoxy such as methoxy, ethoxy, n-propoxy and isopropoxy.

i i f 10 79528

Examples of halogens mentioned in the above formulas are fluorine, chlorine, bromine and iodine. Examples of lower (C 1-3) alkylsulfonyl are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and isopropylsulfonyl. Examples of (C2-4) acylamino are acetylamino, propionylamino, n-butyrylamino and isobutyrylamino. Examples of (C2-10) acyloxy are acetoxy, n-propionyloxy, n-butyryloxy, isobutyryloxy, n-pentanoyloxy, n-hexanoyloxy, n-heptanoyloxy, n-octanoyloxy, n-nonanoyloxy and n-decanoyloxy .

Examples of the above-mentioned acyl groups include • 3- (2,6-dichlorophenyl) - according to the formula Rg-CO- (in which Rg is as defined above). 5-methylisoxazol-4-ylcarbonyl, 4-ethyl-2,3-dioxo-1-piperazinecarbonyl and 2-oxoimidazolidin-1-ylcarbonyl.

R7-NH-CH-CO

Examples of the acyl group according to r9 (R7 and R8 are as defined above) include D-alanyl; D-phenyl-alanyl; -benzyl-N-carbobenzoxy-D-glutamyl-D-alanyl; D-phenylglycyl-D-alanyl; N-carbobenz- *: oxy-D-phenylglycyl; D-alanyl-D-phenylglycyl; -D-glutamyl-D-alanyl, N-carbobenzoxy-D-alanyl-D-phenyl-glyclyl; D-carbamoyltryptophyl-D-phenylglycyl; [N- (2-amino-3- (N-methylcarbamoyl) propionyl) -D-phenyl-Gly; D-N- (2-karbobentsoksiamino-3- (N-methyl-karbamo-yl) propionyl) -D-phenylglycyl; N-carbobenzoxy-D-phenylglycyl-D-phenylglycyl; 2- (2,3-diaminopropionamido) -2-phenylacetyl; D-alanyl-D-alanyl; 2- (2-Ami-no-3- (N-methylcarbamoyl) -propioniamido) acetyl; 2- (2-amino-3-sulfamoyylipropioniamido) -2-phenylacetyl; 2- (2-amino-3- (4-ethyl-2,3-dioxo-l-piperazinecarboxamide) -propioniamido) -2-phenylacetyl; D-2- (4-ethyl-2,3-dioxo-jin 79528 1-piperazinecarboxamide) -2- (4-methoxyphenyl) -acetyl; D-2- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide-3- (N-methylcarbamoyl) propionamido) -2-phenylacetyl; D-2- (2- (4-ethyl-2 (3-dioxo-1-piperazinecarboxamide) acetamido) -2-phenylacetyl, D-2- (3-sulfamoyl-2-benzyloxycarboxamide propionamido) -2-phenylacetyl, D-2- (2-benzyloxycarboxamide-3- (4 -methoxyphenyloxycarboxyamide) propionamido) -2-phenylacetyl, 2- (2-benzyloxycarboxamide-3- (N-methylcarbamoyl) propionamido) acetyl, 2- (N-carbobenzoxy-D-phenylglycylamino) -3- ( N-methylcarbamoyl) propionyl, N-carbobenzoxy-D-alanyl, 2-benzyloxycarboxamido-3- (N-methylcarbamoyl) propionyl, D-2- (4-ethyl-2,3-dithiooxo- 1-piperazinecarboxamide-2-phenylacetyl; 2- (2-aminothiazol-4-yl) -2 - [(· (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) acetyl); (2-phenylacetamido) propionyl, 2- (4-ethyl-2,3-dioxo-: * · *: 1-piperazinecarboxamide) -2-thienyl ethyl, D-2- (4-n- .... : dodecyl-2,3-dioxo-1-piperates sicarboxamide) -2-phenylacetyl; D-2- (4,6-dienyl-2,3-dioxo-1-piperazinecarboxamide) -2-phenylacetyl; D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamide) -2-phenylacetyl; D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamide) -2-thienylacetyl, D-2- (4-n-amyl-6- (S) -methyl-2,3 -dioxo-1-piperazinecarboxamide) -2-thienylacetyl; D-2- (4-ethyl-5- (R) -methyl-2,3-dioxo-1-piperazinecarboxamide) -2-thienylacetyl; D-2- (4-ethyl-5- (S) -methyl-2,3-dioxo-1-pi-.beta.-2. Perazinecarboxamide) -2-thienylacetyl; 2- (8-hydroxy- ** 1,5-naphthyridine-7-carboxamido-2-phenylacetyl; 2- (4-n-octyl-2,3-dioxo-1-piperazinecarboxamide) -2 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (4-hydroxysulfonyloxyphenyl) acetyl; 2- (4-ethyl-2,3-dioxo-1- piperazinecarboxamide) -2- (4-chloro-phenyl) -acetyl, 2- (4-n-octyl-2,3-dioxo-1-piperazinecarboxamide) -2- (4-hydroxysulfonyloxy-phenyl) -acetyl; 4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (4-trimethylsilylphenyl) acetyl, 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (3-chloro- 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxyamido-12,79528 di) -2- (3-chloro-4-hydroxysulfonyloxyphenyl) -acetyl; 2,3-dioxo-1-piperazinecarboxamide) -2- (3-chloro-4-hydroxyphenyl) acetyl, 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (4-benzyloxyphenyl) 2- (4-n-octyl-2,3-dioxo-1-piperazinecarboxamide) -2- (4- hydroxy-phenyl) -acetyl, α-N- (4-ethyl-2,3-dioxo-1-piperazinecarbonyl) -glutaminyl; N- (4- (4-ethyl-2,3-dioxo-1-piperazinecarbonyl) -phenylalanyl; N- (4- (4-ethyl-2,3-dioxo-1-piperazinecarbonyl) -D-lower); 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2 - (, 4-hydroxyphenyl) acetyl, 2,2-bis- (4-ethyl-2,3-dioxo-1-yl), 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (1-cyclohexen-1-yl) acetyl, 2- (4-n-octyl-2,3-piperazinecarboxamide) -dioxo-1-piperazine-carboxamide) -2-thienylacetyl, 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (2-chloroacetamidothiazol-4-yl) acetyl, 2- ( 4-Ethyl-2,3-dioxo-1-piperazinecarboxamide (-2-methyl-thiazol-4-yl) -acetyl, 2- (4-ethyl-2,3-dioxo-1- piperazinecarboxamide) -2- (2-acetamido-thiazol-4-yl) -acetyl, 2- (4-n-octyl-2,3-dioxo-1-piperazinecarboxamide) -2- (2-aminothiazol-4-yl) ) -acetyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2-furylacetyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2 - (2-pyrrolyy yl) acetyl; 2- (4-ethyl-2,3-dithiooxo-1-piperazinecarboxamide) -2- (4-hydroxyphenyl) acetyl; 2- (1,4-n-octyl-2,3-dioxo-1-piperazinecarboxamide) -2- (2-chloroacetamido-thiazol-4-yl) -acetyl; N- (4-ethyl-2,3-dioxo-1-piperazinecarbonyl) -D-methionyl; D-2- (4- (2-phenylethyl) -2,3-dioxo-1-piperazinecarboxamide) phenylacetyl; D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (4-benzoyloxyphenyl) acetyl, 2,5-bis- (4-ethyl-2,3-dioxo-1- piperazinecarboxamide) pentanone-yl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (N-methylcarbamoyl) propionyl; 2,3-bis (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) propionyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3-chloropropionyl; 2- (4-Ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (4-n-octanoyloxy-phenyl) -acetyl; 2- (4-ethyl-2,3-difluoro-1-piperazinecarboxamide) -3-sulfamoylpropionyl; 3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide)) - 3- (1- (methyl-H-tetrazol-5-yl) thio) propionyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) acetyl; D-2- (4- (2-hydroxyethyl) -2,3-dioxo-1-piperazinecarboxamide) -2-phenylacetyl; D-2- (4- (2-chloroethyl) -2,3-dioxo-1-piperazinecarboxamide) -2-phenylacetyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (ethoxycarbonylmethylcarbamoyl) -propionyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (thienylacetamido) -propionyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (2- (1H-tetrazol-1-yl) acetamido) propionyl, 2- (4-ethyl-2,3 -dioxo-1-piperazinecarboxamide) -2- (1H- *; **: tetrazol-1-yl) -acetyl; 2 - ((3-Furfurylideneamino-2-oxoimidazolidin-1-yl) -carboxamido) -2-phenylacetyl, 2 - ((3-furfurylideneamino-2-oxoimidazolidin-1-yl) -carboxamide ) -2- (4-hydroxyphenyl) acetyl; 2 - ((3-furfuryl-lideneamino-2-oxomidazolidin-1-yl) -carboxamido) -2-] - (4-hydroxysulfonyloxy-phenyl) -acetyl; 2 - ((2-Oxo-3- (thiophene-2-aldoimino) -imidazolidin-1-yl) -carboxamido) -2-phenylacetyl; 2 - ((3-furfuryylideeniamino-2-oksoimi-imidazolide-1-yl) carboxamido) -2-thienylacetyl; D-2 - ((3-methylsulfonyl-2-oxoimidazolidin-1-yl) carboxamido) -2-phenylacetyl; 2 - ((3-Furfurylideneamino-2-oxo-imidazolidin-1-yl) -carboxamido) -2- (2-amino-thiazol-4-yl) -acetyl; 2 - ((3-Furfurylideneamino-2-oxoimidazolidin-1-yl) -carboxamido) -2- (2-chloro-acetamidothiazol-4-yl) -acetyl; 2 - ((2-oxo-3- (thiophene-2-aldimino) -imidazolidin-1-yl) -carboxamido) -2-thienylacetyl; 2 - ((3-mesyl-2-oxoimidazolidin-1-yl) carboxamido) -2-thienylacetyl; D-2 - ((3-furfuryylideeniamino-2-oxo-l-yl) carboxamido) propionyl; 2- (4-hydroxy-6-methyl-nicotinamido) -2-phenylacetyl; 2- (4-Hydroxy-6-methyl-nicotinamido) -2- (4-hydroxy-phenyl) -acetyl, 2- (5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxo -pyrido) - (2,3-d) - (pyramidine-6-carboxamido) -2-phenylacetyl; 2- (3,5-dioxo-1,2,4-triazine-6-carboxamido) -2- (4-hydroxyphenyl) acetyl; D-3 - ((2-oxo-3-sulfoimidazolidin-1-yl) -1,4,79528 carboxamido) -2-thienylacetyl; O-2 - ((5-methoxycarbonyl-3-methyl-2-oxoimidazolidin-1-yl) carboxamido) -2-phenylacetyl; D-2 - ((5-benzyloxycarbonyl-3-methyl-2-oxoimidazolidin-1-yl) carboxamido) -2-phenylacetyl; D-2 - ((5-carboxyl-3-methyl-2-oxoimidazolidin-1-yl) carboxamido) -2-phenylacetyl; 2- (coumarin-3-carboxamide) -2-phenylacetyl; 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2- (2-chloro-1-cyclohexen-1-yl) acetyl; D-2- (4-n-amyl-2,3-dioxo-1-piperazinecarboxamide) -2-phenylacetyl; D-2- (4-n-amyl-6 (R) -methyl-2,3-dioxo-l-piperazinecarboxamide) -2-thienylacetyl; 2- (4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamido) -2-phenylacetyl; 2- (4-Hydroxy-7-trifluoromethylquinoline-3-carboxamido-2-phenylacetyl; N- (2- (2-aminothiazol-4-yl) acetyl) -D-phenylglycyl; (6-Bromo-1-ethyl-1,4-dihydro-4-oxothieno (2,3-b) pyridine-3-carboxamido) -2-phenylacetyl; 2- (2- (2 -chloroacetamidothiazol-4-yl-acetamido) -2-phenylacetyl, 2- (2,5-dioxo-1,2,4-triazino-6-carboxamido) -2-thienylacetyl, 2- (2,4-dioxo-pyrimidino-5-carboxamido-2-thienylacetyl, 2- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2-thienylacetamido) -2- phenylacetyl, 2- (2-ureido-2-thienylacetamido) -2-phenylacetyl, 2- (2-ureido-2-thienylacetamido) -2- (4-hydroxysulfonyloxyphenyl) acetyl, 2- (2-ureido-2-thi - * enylacetamido) -2- (4-hydroxyphenyl) acetyl, 2- (N-carbobenzoxypropylamino) -2-furylacetyl, <* - (thienylmethylcarbonyl) alanyl, 2- (4-chlorobenzoylureido) -2- thienylacetyl, 2- (2-thienylacetamido) acetyl, N-benzoyloxycarboxamido-D-alanyl, N- (4-hydroxybenzyl) benzoyl) -D-alanyl; 2- (4-chlorobenzamido) propionyl; 2- (4-aminobenzamido) acetyl; N- (4-ethyl-2,3-dioxo-1-PI-peratsiinikarbonyyli) -metionyyli-D-phenylglycyl; D-2 - ((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) carboxamido) -2-thienylacetyl; 2-ureido-2-thienylacetyl; N-carbamoyl-D-phenylglycyl; 2- (3-methylcarbamoyl-3-methyl-1-ureido) -2-phenylacetyl, 2- (3-methylcarbamoyl-3-methyl-1-ureido) -2- (4-hydroxyphenyl) acetyl; 2- (3-Methylcarbamoyl-3-methyl-1-ureido) -2-thienylacetyl) 79528; 2- (3- (2-hydroxybenzoyl) -1-ureido) -2-phenylacetyl, 2- (3- (2-benzyloxybenzoyl) -1-ureido) -2- (4-hydroxysulfonyloxyphenyl) acetyl; 2- (3- (2-hydroxybenzoyl) -1-ureido) -2- (4-hydroxyphenyl) acetyl; 2- (3- (2-benzyloxybenzoyl) -1-ureido) -2-phenylacetyl, 2- (3- (2-benzyloxybenzoyl) -1-ureido) -2- (4-hydroxyphenyl) acetyl; D-2- (2-benzyloxycarboxamido) -2- (benzyloxycarbonyl) ethanesulfonamido) -2-phenylacetyl; N-mesyl-D-phenylglycyl; 2- (2-aminothiazol-4-yl) -2-ureidoacetyl; 2- (2-Amino-thiazol-4-yl) -2-forma midoasetyyli; 2- (2-aminothiazol-4-yl) -2-acetamido-Acetyl-yl; 2- (2-aminothiazol-4-yl) -2 - ((1-carboxy-1-methyllethoxy) imino) acetyl; 2- (2-aminothiazol-4-yl) -2-pivaloyl-2: **: amidoacetyl; 2- (2-aminothiazol-4-yl) -2- (3-methyl-1- (ureido)) acetyl; 2- (2-Aminothiazol-4-yl) -2 - ((2-methoxycarbonyl-2-methyl-propion) -amido) -acetyl; 2- (2-Amino-thiazol-4-yl) -2- (2- (methoxycarbonyl) -acetamido) -acetyl; 2- (2-Aminothiazol-4-yl) -2 - ((3- (3-thienylidene) amino-2-oxoimidazolidin-1-yl) carboxamido) acetyl; 2-Thienyl-2 - ((3- (3-thienylidene) amino-2-oxoimidazolidin-1-yl) carboxamido) acetyl; 2- (2-aminothiazol-4-yl) -2- (oxamoylamino) acetyl; 2- (2-aminothiazol-4-yl) -2-metoksallyyliamino) acetyl; 2- (2-aminothiazol-4-yl) -2-: (oxaloamino) -acetyl, D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (S) -formyloxybutyryl; D-2 -, (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (S) -hydroxybutyryl, etc.

::: Formula Rio-C-CO-

1 of II

·: * ·: Examples of the acyl group according to NO-R13 (wherein R12 Da R13 are as defined above) are N- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) -D- lower phenyl; N- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) -D-phenylglycyl; 2- (2-aminothiazol-4-yl) -2- (2-aminothiazol-4-yl) -2-methoxy-iminoasetamidoasetyyli; 2- (2-Chloro-acetamidothiazol-4-yl) -2- (2- (2-chloro-acetamidothiazol-79528 sol-4-yl) -2-methoxyiminoacetamido) -acetyl, 2- (2-chloro-acetamidothiazol) -4-yl) -2-methoxyiminoacetyl; 2- (2-amino-notiatsol-4-yl) -2-isopropoxy-methoxyimino acetyl; 2- (2-Amino-thiazol-4-yl) -2-methoxyimino acetyl; 2- (2-aminothiazol-4-yl) -2-methoxyimino acetyl-oxy; 2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl; 2- (4-hydroxyphenyl-propionyl) -2-methoxyimino acetyl; 2-phenyl-2-methoxyiminoacetyl; 2-phenyl-2-oxo-methoxyimino acetyl; 2-thienyl-2-oxy-methoxyimino acetyl; 2-thienyl-2-dichloroacetyloxyiminoacetyl; 2- (4- (f-D-glutamyloxy) -phenyl) -2-oxyiminoacyl; 2- (4- (3-amino-3-carboxypropoxy) phenyl) -2-oxyiminoacetyl; 2-thienyl-2- (3-morpholino-propyloxyimino) -acetyl; 2- (5-chloro-2- (5-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetyl 2- (5-chloro-2-aminothiazol-4-yl) methoxyiminoacetyl; 2-Aminothiazol-4-yl) -2- (1-carboxy-1-methyl-ethoxyimino) -acetyl; 2- (1- (t-butoxycarbonyl) -1-methyl-ethoxyimino) 2- (2-sulfoaminothiazol-4-yl) acetyl, 2- (1- (t-butoxycarbonyl) -1-methylethoxyimino) -2- (2-triphenylmethylaminothiazol-4-yl) acetyl, 2 - (2-chloro-acetamidothiazol-4-yl) -2- (1-methylethoxyimino) -acetyl, 2-methoxyimino-2- (2-hydroxysulfonylamino-thiazol-4-yl) -acetyl, 2- ( 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-phenylacetyl, 2- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamidoacetyl; 2- (2 -Mesylaminothiazol-4-yl) -2- (1-methylethoxyiminoacetyl; 2- (2-aminothiazol-4-yl) -2 - ((carboxy) methoxyimino) acetyl, 2- (2-aminothiazol-4-yl) 4-yl) -2 - ((1-carboxy) ethoxyimino) acetyl, 2- (2-chloroacetamidothiazol-4-yl) -2- (1- (2-trimethylsilylethoxycarbonyl) -1-methyl (ethoxyimino) acetyl; 2- (1- (2-Trimethylsilylethoxycarbonyl) -1-methyl-ethoxyimino-2- (2-tritylaminothiazol-4-yl) -acetyl; 2- (2-aminothiazol-4-yl) -2 - ((1 2- (2-aminothiazol-4-yl) -2 - ((1-methoxycarbonyl-1-methyl) ethoxyimino) acetyl, 2-carbamoyl-1-methyl) ethoxyimino) acetyl, 2 - (2-aminothiazol-4-yl) -2 - ((carbamoyl) methoxyimino) acetyl; 2- (2-aminothiazol-4-yl) -2 - ((tetrazol-5-yl) methoxy- imino) acetyl, 2- (2-aminothiazol-4-yl) -2 - ((methoxycarbonyl) methoxyimino) acetyl, etc.

17 79528 _ C% - CH-CO-

The formula \ m / I

* Examples of the acyl group according to 17 (R17 has the same meaning as defined above) include α-sulfophenylacetyl; οί-hydroxysulfonyloxyphenylacetyl; (X-hydroxyphenylacetyl; N-sulfamoylphenylacetyl; N - (phenoxycarbonyl) phenylacetyl; - (p-tolyloxycarbonyl) phenylacetyl; formyloxyphenylacetyl; N-dimethylsulfamoyl) -2-phenylacetyl, 2-bromo-2-phenylacetyl, 2-azido-2-phenylacetyl, 2-phthalimido, 2-thienylacetyl, 2-azido-2- (3-chlorophenyl) acetyl ; \ 'V, etc.

• * 1: · * Examples of the formula R19-CH2-CO- (R19 means the same as * · defined above) are cyano: 4:.: Acetyl; phenylacetyl; phenoxyacetyl; trifluoromethylthioacetyl; syanometyylitioasetyyli; H-tetrazol-1-yl-acetyl; 2-thienylacetyl; 2- (2-aminothiazol-4-yl) acetyl; 2- (2-klooriasetamidotiatsol-4-yl) acetyl; 4-pyridyylitioasetyyli; 2-thienylthioacetyl; - 3,5-dichloro-1,4-dihydro-4-oxopyridine-1-acetyl; karboksivinyylitioasetyyli; 2- (2-aminomethylphenyl) acetyl; 2- (2-N-karbobentsoksiaminometyylifenyyli) acetyl; 2- (2-ureidometyylifenyyli) acetyl; : 2- (2 - ((2-oxoimidazolidin-1-yl) carbonylamino-methyl) phenyl) acetyl; 2- (2 - ((3-benzylideneamino-2-oxoimidazolidin-1-yl) carbonylaminomethyl) phenyl) acetyl; 2- (5-6-dihydro-1,4-oxazolin-in-2-yl) acetyl; 2- (2,5-dioxo-3-yl) acetyl; 2-sukkinimidoasetyyli; 2- (L- (acetyl) -2,4-dioxo-imidazolin-3-yl) acetyl; and so on.

The amino and / or carboxyl group of the above acyl groups may be protected.

I8 79528

The protecting groups for said amino group are the "amino protecting groups" mentioned below.

Protecting groups for a carboxyl group are all those groups which are generally used as carboxyl protecting groups in the field of (*) - lactam compounds and organic chemistry, in which case their ester moieties are e.g.

methyl, ethyl, propyl, isopropyl, t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, phenacyl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivalo- yloxymethyl, β-methylsulfonylethyl, methylthiomethyl, trityl, β, β, β-trichloroethyl, β-iodoethyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-trimethylsilylethyl, 2-cyanoethyl, trimoyl p-mesylbenzoylmethyl, phthalimidomethyl, propionyl-oxymethyl, 1,1-dimethylpropyl, 3-methyl-3-butenyl, succinimidomethyl, 3,5-di-tert-butyl-4-hydroxybenzyl, mesylmethyl, benzenesulfonylmethyl, phenylthiomethyl , dimethylaminoethyl, pyridine-1-oxido-2-methyl, methylsulfinylmethyl, bis- (p-methoxyphenyl) methyl and 2-cyano-1,1-dimethylethyl.

The object of the invention is to provide the above-mentioned novel monocyclic compounds, so that there are no restrictions on the choice of the protecting group. However, benzyl, β, β, β-trichloroethyl, 2-trimethylsilylethyl, benzhydryl, t-butyl, p-nitrobenzyl and p-methoxybenzyl are particularly preferably used.

The amino protecting groups of the above formulas are preferably those used in the field of β-lactam and peptide synthesis. Examples are aromatic acyl groups such as phthaloyl, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert-butylbenzenesulfonyl, benzenesulfonyl and toluenesulfonyl, aliphatic acyl groups such as formyl, acetyl, propionyl, chloroethyl, propionyl, mono- 19 -nisulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl-succinyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl and methoxycarbonyl, nitro-nitro, trity, such as 4-nitrobenzylidene, di- or trialkylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and p-nitrobenzyl. The choice of this protecting group, as well as the carboxy protecting group, is not critical to the invention. However, monochloroacetyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl and p-nitrobenzyloxycarbonyl are particularly preferably used.

Among the optionally acylated or protected amino groups represented by R 1 in the above formulas, those groups which are better suited to achieve an antibacterial and β-lactamase inhibitory effect may be represented by the formula ‘A - C - CONH -

A

wherein A is hydrogen, a lower alkyl group such as methyl, ethyl or isobutyl, an alicyclic group such as cyclohexyl or cyclohexenyl, an aryl group such as phenyl, an aralkyl group such as phenoxybenzyl, or a heterocyclic group such as thienyl, benzothienyl, pyrrolyl, solyl, piperazinyl, thiazolyl, tetrazolyl or oxatiano, wherein this group A may have one or two substituents, e.g. amino, lower alkyl, lower alkoxy-phenoxy, oxo, hydroxyl, halogen or chloroacetamido. W is in the case where Z is hydrogen, an optionally esterified carboxyl group, a sulfo group, a sulfamoyl group, a hydroxy-sulphonyloxy group, an optionally protected amino group, an amido group such as arylcarboxamido, (e.g. phenylcarboxy-siamido) or a lower alkylcarboxamido group or heterocyclic carboxamido group (such as 2,3-dioxo-1-piperazine) carboxamido, imidazolidinecarboxamido, oxoimidazolidinecarboxamido, (isooxazol-4-yl) carboxamido, (2-aminothiazol-4-yl) -methylcarboxamido or 3- (2,3-dioxo-1-piperazinecarboxamide-2-carbobenzoxyaminopropionamido, or W and Z together form a group of formula N-X'-G (wherein X 'is an oxygen or sulfur atom or a sulfoxide group) , and G is a lower alkyl group, a carboxy- (lower) alkyl group such as O, OC-dimethyl-OC-carboxymethyl, an aryl group such as phenyl, or an acyl group such as acetyl or the formula -C

W Z can be a direct bond or O

* n -C-. In the above formula, the lower alkyl group A may preferably be a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and may have a substituent other than those mentioned above, e.g., N-methylcarbamoyl, carbobenzyloxyamino, an aryl group such as phenyl, or a heterocyclic group such as tetrazolylacetamido, 4-ethyl-2,3-dioxo-1-piperazinecarboxamido, or 1,2-diazole which may have phenyl, methyl or ethyl in the 3-position. The possible halogen substituent of group A may be fluorine, chlorine or bromine, the lower alkyl group is methyl and ethyl, and the lower alkoxy group is methoxy and ethoxy. The optionally protected amino group W is chloroacetylamino, aralkylamino and aralkyloxycarbonylamino. The heterocyclic portion of the heterocyclic carboxyamido group W may be substituted, wherein the substituent may be phenyl, a (C 1-12) alkyl group, a saturated alicyclic group, a (C 2 -C 6) alkenyl group, an arylcarbonyl group optionally substituted with a lower alkoxy group such as methoxy or furfurylideneamino, sulfo, alkoxycarbonyl, aralkyloxycarbonyl or carboxyl.

and 21,79528

The lower alkyl moiety of the lower alkylcarboxamide group W is preferably a straight-chain or branched alkyl group having 1 to 4 carbon atoms, which may be substituted by a halogen atom such as fluorine, chlorine or bromine.

Of the above-mentioned compounds of formula (I), those in which A is phenyl, phenoxy, thiazolyl, thienyl or piperazinyl are preferably used, and A is further substituted by amino, lower alkyl or lower alkoxy, and optionally in the position is amino or methoxyimino.

Because the compounds (I) have a sulfone group, they can generally form salts with bases. Therefore, the compounds (I) can be recovered as salts, and the recovered salts can be converted into the free form or other salts. In addition, the compounds (I) obtained in free form can be modified. . salts. Examples of the above bases include size inorganic bases such as lithium, potassium, sodium, calcium and ammonium bases, and organic bases such as pyridine, collidine, triethylamine, tetra-n-butylammonium hydroxide and triethanolamine.

The invention also includes salts of the compounds (I). A method for converting compounds in the form of a salt to the free form is, for example, a method based on the use of an acid. Suitable acids for use depend on the type of protecting group and other conditions, but inorganic acids such as hydrochloric, sulfuric and phosphoric acid, and organic acids such as formic, acetic and p-toluenesulfonic acid are often used. Acid ion exchange resins are also used. Commonly used solvents include hydrophilic organic solvents such as acetone, tetrahydrofuran, methanol, ethanol and dioxane, water and solvent mixtures.

22 79528

Depending on the conditions, stereoisomers (e.g., D-isomer, L-isomer) may be present in compounds (I). In this case, the various isomers as well as mixtures thereof are within the scope of the invention.

Both pure isomers and mixtures thereof can be used as drugs. If a mixture of isomers is obtained, each isomer can be isolated, if necessary, by applying conventional methods to achieve the desired separation.

The compounds (I) thus obtained are useful drugs. Thus, they have an antagonistic effect on some Gram-positive and Gram-negative bacteria.

With respect to the acute toxicity of the compounds (I) of the invention, the intravenous LD50 values in mice are 500 mg / kg or more.

The compounds (I) of the invention can be advantageously used in the treatment of mammals (e.g. mice, rats, humans) if the above-mentioned bacteria have caused an infection therein.

4. I

The compounds (I) of the invention can be used as medicaments against bacterial infections, e.g. in the treatment of infectious diseases of the respiratory tract, infectious diseases of the urinary tract, purulent diseases, infectious diseases of the hepatic tract, infectious diseases of the intestine as well as infectious and gynecological diseases. The daily dose is about 20 to about 200 mg / kg of Compound (I), preferably divided into 2 to 4 separate doses, each unit being about 5 to about 100 mg / kg. The compounds (I) or their physiologically tolerable salts can be administered orally, e.g. as tablets, capsules or dragees prepared in a manner known per se, or administered parenterally, e.g. by preparing injectable preparations which are added to a sterile carrier using conventional methods.

23 79528

The compounds (I) of the present invention have β-lactamase inhibitory activity, so that they can be used as β-lactamase inhibitors.

The compounds (I) according to the invention are used in cases where β-lactam antibiotics are administered for the treatment and prevention of bacterial infections in humans or domestic animals.

When the dosage form compounds (I) of the invention are used, they are used before or after the administration of β-lactam antibiotics or in admixture with these antibiotics before their administration. They can also be prepared in dosage forms as mixtures with β-lactam antibiotics. In this case, useful β-lactam antibiotics include e.g. Benzylpenicillin, phenoxymethylpenicillin, sulbenicillin, carbenicillin, ampicillin, amoxicillin, mesillinam, cloxacillin, di-cloxacillin, piperacillin, apalsillin, cefecamoxin, cefaloridine, kafalotin, cefazolin, cefazoline, cefazolin, cefazolin cefmetazole, cefsulodine, cefachlor, cefta-tricin, cefotaxime, cefmenoxime, ceftadicin, cefteoxime and other known penicillins and cephalosporins, as well as hetacillin, metampicillin, talampicillin, carivacillin, pindivillin, carfecillin, carfecillin tab- .... l in the form of tablets, capsules, etc. using conventional methods. Preferably they are used as injections of salts or hydrates. When using such methods of use, the compounds (I) according to the invention can be used in amounts of 0.1 to 10 parts by weight per part by weight of the lactam antibiotic, preferably in a ratio of 1 to 1/8, e.g. 1/5 or 1/6. The compounds of the invention are generally administered in daily doses of 50 to 1000 mg, i.e. more generally in daily doses of 20 to 100 mg.

150 mg / kg, divided into e.g. 1 to 6 doses, usually 2 to .4 separate doses.

J

24 79528

The 1-sulfo-2-oxoazetidine derivatives (I) according to the invention can be prepared, e.g., by sulfonating the compound (II). The sulfonation reaction is carried out by attaching a sulfone group, e.g. by contacting compound (II) with sulfuric anhydride, i.e. sulfur trioxide or a reactive derivative thereof, e.g.

Reactive derivatives of sulfur trioxide include, for example, sulfur trioxide-N, N-dimethylformamide, sulfur trioxide-pyridine, sulfur trioxide-dioxane, sulfur trioxide-trimethylamine, or an adduct of sulfur trioxide and chlorosulfonic acid.

In the above reaction, sulfur trioxide or a reactive derivative thereof is added in an amount of about 1 to about 5 moles, preferably about 1 to about 2 moles per mole of the compound (II).

The reaction temperature is about 0 to about 80 ° C, preferably about 10 to about 40 ° C. A solvent can be used in the reaction. Suitable solvents include ethers such as dioxane, tetrahydrofuran and diethyl ether, esters such as ethyl acetate and ethyl formate, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane and amide such as dimethyl , and other conventional organic solvents, alone or in combination. After the reaction, the compounds (I) can be recovered in any desired degree of purity by carrying out a purification / separation treatment of the reaction mixture in a manner known per se, e.g. as solvent extraction, recrystallization and / or chromatography. The starting compounds (II) can be reacted as various salts, esters, silyl derivatives, etc. Silyl derivatives can be prepared by silylation with a silylating agent using any known substance, usually using a silyl compound having the general formula 25 "R" - Si - Y (A) R '' 'wherein R' and R "are a lower alkyl group or a lower alkoxy group, R" '' is halogen, phenyl, a lower alkoxy group or a lower alkyl group and Y is a reactive group to be liberated from the silylating agent .

In the silylating agent represented by the above formula (A) ____: the lower alkyl group may be e.g. methyl,: chloromethyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, the halogen may be e.g. chlorine or bromine; the reactive group to be released from the silylating agent may be, in addition to the above-mentioned halogen, e.g.

N- (trimethyl-silyl) trifluoriasetimidoyyli-oxy group; N- (trimethylsilyl) -asetamidoyylioksiryhmä; halogen; an acylamino group such as formylamino, acetylamino, propionylamino, butylamino or trifluoroacetylamino, (trialkylsilyl) amino group; such as trimethylsilylamino or (chloromethyltrimethylsilyl) amino; amino; alkyl-amino group; such as methylamino; ethylamino or propylamino; N, N-dialkylamino group; such as Ν, Ν-dimethylamino, N-chloromethyl-N-methylamino »Ν, Ν-diethylamino; N, N-dipropylamino; N-methyl-N-ethylamino; N-methyl-N-:. propylamino or N-ethyl-N-propylamino; or a heterocyclic group such as imidazolyl.

Some examples of the silyl compounds described above include Ν, Ο-bis- (trimethylsilyl) -trifluoroacetamide; Ν, Ο-bis (trimethylsilyl) -acetamide; bis (dimethylisopropylsilyl) acetamide; trimethylsilyl-acetamide; bis- (dimethyl-tert-butylsilyl) -acetamide, N-methyl-N-trimethylsilyl-acetamide; N-methyl-N-trimethylsilyl-trifluoroacetamide) N-trimethylsilyldimethylamine; hexamethyldisilazane; 1,3-bis (chloromethyl) -1,1,3,3-tetrametyylidisilatsaani; N-trimethylsilylimidazole, 26,79528 trimethylchlorosilane; triethylchlorosilane; dimethyl-dichlorosilane; dietoksikloorisilaani; tert-butyl-methylchlorosilane; isopropyylidimetyylikloorisilaani; dimethylphenylchlorosilane or chloromethyldimethylchlorosilane.

When tert-butyldimethylchlorosilane or isopropyldimethylchlorosilane is used among these, the corresponding silyl derivatives can be isolated as stable. In the above reaction, at least one equivalent of the silyl compound (A), preferably 1 to 3 equivalents per equivalent of the compound (II) is used. The reaction temperature is in the range of 0 to about 50 ° C, preferably up to 38 ° C, usually room temperature, and the reaction time is from several minutes to 24 hours. The reaction is preferably carried out e.g.

· In ethyl acetate, dioxane, tetrahydrofuran, N, N-dimethylacetamide, Ν, Ν-dimethylformamide, dichloromethane, chloroform, benzene, toluene, acetone, methyl ethyl ketone or acetonitrile in any reaction, or in any other mixture thereof, or in any other solvent . The reaction may also be carried out in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or potassium carbonate, or an organic base such as a trialkylamine such as triethylamine; tributylamine; tribenzylamine; N-methylmorpholine or N-methylpiperidine; an organic tertiary amine; such as N, N-dialkylaniline; N, N-diaikyylibentsyyliamiini; pyridine; picoline or rutidine; or an organic base such as 1,5-diazabicyclo (2,2,2-octane or 1,8-diazabicyclo- (5,4,4) -undecene-7) In the case where the base is liquid, it can also be used as a solvent. from the obtained 1-silyl derivative of the compound (II) in which R 2 is a protected amino group, a 1-silyl derivative of the desired compound (II) can be obtained by deprotection and subsequent acylation.

t 27 79528

The R3trR4-Nn oo3h-1-sulfo-2-oxoazetidine derivatives of the following formula (IV) of the invention can also be prepared, e.g., by acylation of compound (III) by reacting this compound (III) with an acylating agent. The acylating agent used in the reaction may be an organic carboxylic acid or a reactive derivative thereof having an acyl group R3.

____: Reactive derivatives of organic acid are e.g. acid anhydrides, active amides and active esters. Reactive derivatives of these; V organic acids are, for example; the following: 1) Acid anhydrides:

Acid anhydrides include e.g. mixed anhydrides of hydrohalic acid (e.g. hydrochloric acid or hydrobromic acid) with monoalkyl carbonate, aliphatic carboxylic acid (e.g. acetic acid, pivalic acid, valeric acid, symmetanoic acid and isopentanoic acid or trichloroacetic acid) or aromatic carboxylic acid (e.g.

·. *. · 2) Activated amides:

Activated amides include the amides pyrazole, imi :. with dabsol, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc.

3) Activated esters:

Among the activated esters, e.g. esters such as methyl, ethyl, methoxymethyl, propargyl, 4-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl and mesylphenyl esters; as well as esters of acids such as the above-mentioned carboxylic acid with 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-carboximide and N-hydroxyphthalamide.

28 79528 l

Suitable reactive derivatives of organic acids are selected from the above, depending on the type of acid used. When free acid is used as the acylating agent, the reaction is preferably carried out in the presence of a condensing agent. Examples of the condensing agent include N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethyl-carbodiimide; N-cyclohexyl-N- (4-diethylaminocyclohexyl) -carbodiimide and N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide.

The acylation is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine and other conventional organic solvents which are inert to the reaction. Among these, hydrophilic solutions can be used as mixtures with water.

The acylation is carried out in the presence of an inorganic base, e.g. sodium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, or in the presence of an organic base, for example a trialkylamine such as trimethylamine, triethylamine, tributylamine; N-methylmorpholine or N-methylpiperidine; or an organic tertiary amine such as N, N-dialkylaniline, N, N-dialkylbenzylamine, pyridine, picoline or lutidine, tetra-n-butylammonium hydroxide or 1,5-diazacyclo (4,3,0) non-5-ene, 1, 4-diazabicyclo- (2,2,2) octane or 1,8-diazabicyclo (5,4,4) undecene-7.

When the base or the above-mentioned condensing agent is liquid, it can also be used as a solvent. The reaction temperature is not critical, but the reaction is usually carried out under cooling or at room temperature.

In the case where the reactive derivative at the amino group of the starting material (III) or a salt or acylating agent thereof contains at least one asymmetric carbon atom. «29 79528 min, the corresponding stereoisomers alone can be acylated as well as mixtures thereof. In the event that the acylation results in a mixture of the corresponding isomers, the various isomers may, if desired, be isolated by conventional means, by column chromatography or recrystallization.

The starting compound (III) can also be used in the acylation reaction as a salt or a silyl derivative thereof. Examples of said salt include those mentioned above in connection with the salts of Compound (I), and examples of silyl derivatives mentioned above.

- In the case where the starting compound used in the acylation reaction is a salt, the compound (IV) can also optionally be obtained as a salt. In the case where this compound is obtained: as a salt, this salt can also be converted into another salt by applying the same method as in exchanging the salts of the above-mentioned compound (I).

The compound (IV) recovered as a salt can also be converted into the free form, in which case the same method as for the conversion of the salt of the above-mentioned compound (I) into the free form can be applied.

Protecting compounds (I) are valuable intermediates in the synthesis of useful drugs and can be converted to unprotected compounds (I), for example, by deprotection.

The protecting groups can be selectively removed from the azetidine derivatives (I) by applying methods known per se, based on, for example, the use of an acid or base, reduction, the use of hydrazine, the use of thiourea or sodium N-methyldithiocarbamate. The acid-based method uses, depending on the type of protecting group and other deprotection conditions, e.g., an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or an organic acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, propionic acid, toluenesulfonic acid, etc., acidic ion exchange resins, etc. Inorganic bases such as hydroxides of alkali metals (sodium, potassium, etc.) or alkaline earth metals (e.g., calcium, magnesium, etc.) are used in base-based methods depending on the type of protecting group and other conditions. carbonates, or organic bases such as metal alkoxides, organic amines, quaternary ammonium salts or basic ion exchange resins, etc.

; When performing the above-mentioned method based on the use of an acid or a base in a solvent, the solvent is usually a hydrophilic organic solvent, water or a solvent mixture.

Depending on the type of protecting group and other conditions, the reduction method uses a metal (e.g., tin, zinc, etc.) or a metal compound (e.g., chromium chloride, chromium acetate, etc.) in combination with an acid such as an organic or inorganic acid (acetic acid, propionic acid, hydrochloric acid, etc.). or a metal catalyst is used in the catalytic reduction. Catalysts which can be used as catalysts are, for example, platinum catalysts (such as platinum wire, platinum sponge, platinum-on carbon, platinum oxide, colloidal platinum, etc.), palladium catalysts (e.g. palladium sponge, palladium-on-palladium , palladium-silica gel, colloidal palladium, etc.), reduced nickel, nickel oxide, Raney nickel, Urushihara nickel, etc.

The reduction method based on the use of metal and acid uses a metal compound (e.g., an iron or chromium compound) and an inorganic acid (e.g., hydrochloric acid) or an organic acid (e.g., formic acid, acetic acid, propionic acid, etc.). The reduction method is usually carried out in a solvent. When using the catalytic reduction method) ί 31 79528, the reaction is usually carried out in the presence of alcohol (e.g. methanol, ethanol, propyl alcohol, isopropyl alcohol, etc.), ethyl acetate, etc. The method based on the use of metal and acid is usually carried out in the presence of water, acetone etc., but when the acid is liquid, it can also be used as a solvent.

The reaction is usually carried out in the temperature range between cooling and heating.

When the protecting group is an organic carboxylic acid group and the carbon atom adjacent to the carbonyl group has a substituent such as free amino, hydroxyl, mercapto, carboxyl, sulfo, etc., a treatment is preferably first performed to emphasize the effect of the group adjacent to the substituent group so that By way of example, if the substituent of a carbon atom adjacent to the carbonyl group is a free amino group, this free amino group is first converted to a thioureido group before the deacylation reaction is carried out. , but may be selected on the basis of the type of protecting group, the deprotection method used, etc., although the reaction is preferably carried out under cooling or slight heating.

In the case where R 1 is a carboxyl-containing group, there are cases in which the derivative at the carboxyl function is converted to a free carboxyl group during the reaction, and these cases also fall within the scope of the invention.

The resulting unprotected compound (I) can be converted into the desired salts using conventional methods.

The starting compounds (II) and (III) can be prepared, e.g., by the following methods.

32 79528 The starting compound (II) can be easily prepared, e.g., in the case where R4 is an acyloxy group, by applying the method described in Tetrahedron Letters 1978, 4059 or Japanese Unexamined Patent Application No. 76570/1979. In the case where R4 is a substituted dithio (-S-S-R5) group, the method described in Chemical Communication 1971, 845 or a method analogous to this method may be applied, or in that case. that R 4 is a group other than acyloxy or substituted dithio, the method described in Annalen der Chemie 1974, 539 can be applied, applying the following alternative synthetic routes (1) and 2).

1)

X X X

R l_s0Kc R-f — Protecting group H N 4 - ^ * 4

• substitution2 deletion f I

J- NH d ^ ~ NH J ~~ NH

O O

(II ') Acylation «·

X R

b> tt

<0 — NH O

2)

Ro-f-Y0ÄC Deprotection of H-N - + - T ° Ac R-i-f0Ac 8 2 Acylation 3 (II "). 0 ^ ~ NH Cl ~ m IV '> (VI'> - substitution 33 79528

f R

r3 — r 4

J— NH O

(II '')

In lime in the reaction formulas described above, R 2, R 3, R 4 and X have the same meaning as defined above, and R 8 is a protected amino group.

The following examples, comparative examples and experimental examples further illustrate the invention. In these examples, PMR spectra were measured using Varian HA 100 (100 MHz), EM 390 (90 MHz) and T 60 (60 MHz) instruments, using tetramethylsilane as a reference standard, b-values are expressed in parts per million (ppm). In the context of chemical transition data, s means singlet, br.s. broad singlet, d doublet, dd double doublet, t triplet, q quartet, m multiplet, ABq quartet of AB pattern, J coupling constant, THF tetrahydrofuran, DMP dimethylformamide, DMSO dimethyl sulfoxide, and arom. aromatic.

Silica gel column chromatography used Kiesel Gel 60 (Art. 9385, 230-400 Mesh, Merck Co., West Germany), and elution was performed by thin layer chromatography (TLC). TLC used HPTLC Kiesel Gel 60 F254 plate (Art. 5642, Merck Co., West Germany) and the same eluent as column chromatography and UV detector.

Fractions containing the desired compound having the same Rf value as the main spot on the TLC plate on the TLC plate were collected with the reaction solution to be column chromatographed.

XAD-II column chromatography used a 20% aqueous solution of ethanol1 as eluent. Fractions containing the desired compound causing an absorbance at 254 nm in the UV spectrum using a LKB UVICORD 2 instrument were collected, followed by lyophilization.

Experimental Example "Determination of the inhibitory concentration required to inhibit enzyme activity by 50%."

The β-lactamase produced by the microorganism Enterobacter cloacae PN 1 282 is used as a typical example of cephalosporinase. β-Lactamase is incubated in 0.05 M phosphate buffer (pH = 7) with a suitable diluted solution of inhibitor for 10 minutes at 30 ° C. An amount of cephalothin sufficient to give a final concentration of 0.1 mM is then added and the enzymatic reaction is allowed to proceed for 10 minutes. Enzyme activity is determined by a microiodometric method (Journal of General Microbiology, Vol. 33, page 121, (1963)). The inhibitory concentration required to inhibit the activity of the enzyme by 50% is then expressed as I50. The values of Enterobacter cloacae 150 in the microorganism are shown in the following table.

table 1

Compound I50 (^ / ml)

Sodium (3R, 4R) -4-methylthio-3- (2- (2-amino-thiazol-4-yl) -2- (1-carboxy-1-methylethoxyiminoacetamido) -2-oxoazetidine-1- sulfonate 0.19

Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoacetidine-1-sulfonate 0.3

Sodium (3R-4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine-1-sulfonate 0.027 1 35 79528

Sodium (3R, 4R) -3- (3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarboxamido) -4-methylthio-3-oxyazetidine-1-sulfonate 0.045

Comparative Example 1 (35,45) -4-Acetoxy-3-benzyloxycarboxamido-2-oxoazetidine 21.9 g of methyl (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine-1 - (CC-isopropylidene) acetate with ozone in 400 ml of methylene chloride until the reaction solution turns blue, then 10 ml of methyl sulphide and a little sodium methoxide in 350 ml of methanol are added. The reaction gives 10.6 g of (3S, 4S) -4-acetoxy. 3-benzyl-oksikarboksamido-2-oxoazetidine.

KBr IR δ cm -1: 3480, 3430, 1815, (olake), 1800, 1770, max 1725, 1695, 1522, 1260, 1240 PMR (CDCl 3, ppm); 2.13 (s, CH 3), 4.80 (dd, J = 2.8Hz, C3-H), 5.20 (s, -CH2-), 5.90 (d, J = 2Hz, C4-H), 6.10 (d, J = 8Hz, NH), 7.26 (broad , s, NH), 7.43 (s, arom. H)

Comparative Example 2 (35,45) -4-Acetoxy-3-phenoxyacetamido-2-oxoacetidine As described in Comparative Example 1, 5 g of methyl (3S, 4S) -4-acetoxy-3-phenoxyacetamido-2-oxoacetidine-1- (A -isopropylidene) acetate to give 2.1 g of (3S, 4S) -4-acetoxy-phenoxyacetamido-2-oxoazetidine.

KBr IR ^ citT1; 3325, 1805, 1760, 1745, 1670, 1530, 1230, max 1218 PMR (CDCl 3, ppm); 2.17 (s, CH 3), 4.62 (s, -CH 2 -), 5.03 (dd, J = 2.7 Hz, C 3 -H), 6.03 (d, J = 2 Hz, C 4 -H), 6.95-7.80 (m, NH, arom H) 36 79528

Comparative Example 3 (3R, 4R) -4-Methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine In an aqueous solution of acetone, 1 g of methyl (3R-4R) -4-methylthio-3-phenoxyacetamido-2-oxoazetidine-1-isopropylidene) is treated with acetate with 1.2 g of potassium permanganate and 2 ml of acetic acid to give 0.486 g of (3R, 4R) -4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine.

KBr IR P cm -1; 3290, 1770, 1675, 1525, 1290, 1275, 1215 max PMR (DMSO-d 6, ppm); 3.16 (s, CH 3), 4.53 (s, -CH 2 -), 5.16 (d, J = 5Hz, C4-H), 5.71 (dd, J = 5.10Hz, C3-H), 6.80-7.43 (m, arom. H), 8.35 (d, J = 10Hz, NH), 9.51 (S, NH)

. I

Comparative Example 4 (3R, 4R) -3-Benzoyloxycarboxamido-4-methylsulfonyl-2-oxoazetidine As described in Comparative Example 3, 4.5 g of methyl (3R, 4R) -3-benzyloxycarboxamido-4-methylthio-2- oxoacetidine 1- (O-propylidene) acetate to give 2.3 g of (3R, 4R) -3-benzoyloxycarboxamido-4-methylsulfonyl-2-oxoacetidine.

KBx IR P cm -1; 3320, 3275, 1765, 1688, 1512, 1292, 1275, max 1252, 1230 PMR (DMSO-d 6, ppm); 2.96 (s, CH 3), 5.07 (d, J = 5Hz, C 4 -H), 5.17 (S, -CH 2 -), 5.50 (dd, J = 5.10 Hz, C 3 -H), 7.42 (s, arom. H), 7.76 (d, J = 10 Hz, NH), 9.40 ( s, NH)

Comparative Example 5 (3R, 4R) -4-Methylsulfinyl-3-phenoxyacetamido-2-oxoacetidine Treat 6 g of methyl (3R, 4R) -4-methylthio-3-phenoxyacetamido-2-oxo-37 as described in Comparative Example 1 79528 azetidine-2- (N, N-isopropylidene) acetate to give 1.34 g of (3R, 4R) -4-methylsulfinyl-3-phenoxyacetamido-2-oxoacetidine.

KBr IR>) cm-1; 3275, 1765, 1665, 1530, 1212 max PMR (DMSO-d 6, ppm); 2.58 (s, CH 3), 4.70 (s, -CH 2 -), 4.92 (d, J = 5Hz, C 4 -H), 5.75 (dd, J = 5.10Hz, C 3 -H), 6.93-7.65 (m, arom. H), 8.61 (d, J-10Hz, NH), 9.28 (S, NH)

Comparative Example 6 (3R, 4R) -4-Ethylsulfinyl-3-phenoxyacetamido-2-oxoacetidine As described in Comparative Example 1, 3.92 g of methyl (3R-4R) -4-ethylthio-3-phenoxyacetamido-2-oxoacetidine are treated. thidine-1- (* - isopropylidene) acetate to give 1.36 g of (3R, 4R) -4-ethylsulfinyl-3-phenoxyacetamido-2-oxoacetidine.

KBr IR>) cm -1; 3310, 3160, 1760, 1685, 1208 max PMR (DMSO-d 6, ppm); 1.23 (t, J = 8Hz, CH 3), 2.70 (q, J = 8Hz, -CH 2 -) , 4.65 (s, -CH 2), 4.75 (d, J = 5Hz, C 4 -H), 5.78 (dd, J = 5.10Hz, CH 3 -H), 6.85-7.63 (m, arom. H ), 9.10 (d, J = 10Hz, NH), 9.18 (s, NH).

Comparative Example 7 (3R, 4S) -4-ethylthio-3-phenoxyacetamido-2-oxoacetidine and (3R, 4R) -4-ethylthio-3-phenoxyacetamido-2-oxoacetidine ____ To a solution of 1.39 g (3S, 4S ) -4-Acetoxy-3-phenoxy-acetamido-2-oxoazetidine in 60 ml of 80% alcohol is added under ice-cooling and dropwise addition of 5 ml of an ethanol solution containing 0.441 g of sodium ethyl sulphide. The mixture is stirred for 30 minutes under ice-cooling and then for 15 minutes at room temperature, after which the ethanol is removed by distillation under reduced pressure, and the aqueous layer is extracted twice with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified on a silica gel column (2: 1 mixture of n-hexane and ethyl acetate as eluent) to give 0.680 g of (3R, 4S) -4-ethylthio-3-phenoxyacetamido-2-oxoazetidine. nujoli IR V cm-1; 3270, 3150, 1752, 1659 max PMR (CDCl 3, ppm); 1.27 (t, J = 7Hz, CH3), 2.62 (Q, J = 7Hz, -CH2-), 4.46 (s, -CH2-), 4.80 (d, J = 2Hz, C4-H), 4.83 (dd, J = 2.9Hz, C 3 -H), 6.70-7.40 (m, arom. H, NH), 7.68 (d, J = 9Hz, NH) and 0.164 g of (3R, 4R) -4-ethylthio-3 -fenoksiasetamido-2-oxo-azetidine.

KB it IR ^ cm-1; 3260, 1770, 1725, 1665, 1525 max PMR (CDCl 3, ppm); 1. 23 (t, J = 7Hz, CH 3), 2.52 (q, J = 7Hz, -CH 2 -), 4.66 (s, -CH 2 -), 5.05 (d, J = 5 Hz, C 4 -H), 5.75 (dd, J = 5.10 Hz, C 3 -H), 6.60 (broad s, NH), 6.90-7.70 (m, arom. H, NH).

Comparative Example 8 (3R, 4S) -4-ethylsulfinyl-3-phenoxyacetamido-2-oxoazetidine

To a solution of 0.224 g of (3R, 4S) -4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of methanol is added 0.16 ml of a 30% aqueous solution of hydrogen peroxide, and the mixture is stirred at room temperature for 4 hours. 0.1 ml of a 30% aqueous solution of hydrogen peroxide is then added, after which the mixture is stirred for a further 4 hours and then 10 ml of water are added. Extract with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of (3R, 4S) -4-ethylsulfinyl-3-phenoxy6-ethamido-2-oxoazetidine.

KB ΐ IR ^ cm-1; 3350, 3270, 1765, 1690 max PMR (DMSO-d 6, ppm); 1.22 (3H, t, J = 8Hz, CH3), 2.75 (q, J = 8Hz, 39,79528 -CH2-, 4.65 (s / -CH2-), 4.78 (d, J = 2Hz, C4-H), 5.15 (dd, J = 2.10 Hz, C 3 -H), 6.93-7.60 (m / ar.H), 8.95 (s, NH), 9.08 (d, J = 10 Hz, NH).

Comparative Example 9 (3R, 4S) -4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine

To a solution of 0.494 g of (3S, 4S) -4-acetoxy-3-phenoxyacetamido-2-oxoazetidine in 14 ml of 50% methanol is added 0.51 g of sodium methyl sulfinate, and the mixture is stirred at room temperature for 18 hours. Methanol is distilled under reduced pressure to give 222 mg of (3R, 4S) -4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine.

KBr IR 1 cm -1; 3290, 1798, 1670, 1525, 1305, 1130, max PMR (DMSO-d 6, ppm); 3.08 (s, CH 3), 4.60 (s, -CH 2 -), 5.02 d, J = 2Hz, C4-H), 5.23 (dd, J = 2.9Hz, C3-H), 6.95-7.63 (m, arom. H), 9.05 (d, J = 9Hz, NH), 9.28 (s, NH) .

Comparative Example 10 (3R, 4S) -3-Benzyloxycarboxamido-4-methylsulfonyl-2-oxoazetidine Treat 1.4 g of (3S, 4S) -4-acetoxy-3-benzyloxy-carboxamido-2-oxoazetidine 0.5 g of sodium methylsulfinate as described in Comparative Example 9 to give 0.75 g of (3R, 4S) -3-benzyloxycarboxamido-4-methylsulfonyl-2-oxoazetidine as colorless prisms.

Sp. 178-180 ° C (decomposes).

S KBr 1 IR v cm-1; 3300, 1800, 1695, 1530, 1300, 1265, 1115 max PMR (DMSO-d 6, ppm); 3.06 (s, CH 3), 4.82 (dd, J = 8.2 Hz, C 3 -H), 5.00 (d, J = 2 Hz, C 4 -H), 5.16 (s, -CH 2 -), 7.43 (s, arom. H), 8.33 (d, J = 8Hz, NH), 9.33 (broad s, NH) 40 79528

Comparative Example 11 (3S, 4S) -3-Benzyloxycarboxamido-4-methoxy-2-oxo-azetidine (A) and (3S, 4R) -3-Benzyloxycarboxamido-4-methoxy-2-oxo-azetidine (B)

Dissolve 3 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoathetidine in 30 ml of methanol, then add 2.36 g of zinc acetate and boil the mixture for 45 minutes under reflux. The solvent is removed by distillation, and the organic layer is separated after adding ethyl acetate and water. The organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 1.37 g of (3S, 4S) -3-benzyloxycarboxamido-4-methoxy-2-oxo-azetidine (A) and 0 .82 g of (3S, 4R) -3-benzyloxycarboxamido-4-methoxy-2-oxo-azetidine (B).

(A). KBr IRV cm’1; 3370, 3320, 1775, 1758, 1690 max PMR (DMSO-d 6, ppm); 3.26 (s, CH 3), 4.23 (dd, J = 1.5.9 Hz, C 3 -H), 4.79 (d, J = 1.5 Hz, C 4 -H), 5.03 (s, -CH 2 -) # 7.33 (s, aroma H), 7.94 (d, J = 9Hz, NH), 8.86 (s, NH) B) KBr IR) cm -1; 3320, 3240, 1768, 1740, 1720, 1700 max PMR (DMSO-d 6, ppm) 3.23 (s, CH 3), 4.79 (dd, J = 4.10 Hz, C 3 -H), 4.91 (d, J = 4 Hz, C 4 -H), 5.03 (s, -CH 2 -), 7.33 (s , arom. H), 7.87 (d, J = 10 Hz, NH), 8.86 (s, NH).

Comparative Example 12 (3S, 4S) -4-methoxy-3-phenoxyacetamido-2-oxoacetidine (A) and (3S, 4R) -4-methoxy-3-phenoxyacetamido-2-oxoacetidine (B) 41,79528

Applying the procedure of Comparative Example 11, but using 1 g of (3R, 4R) -4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine and 1.11 g of zinc acetate, 0.574 g of (3S, 4S) -4-methoxy-3 -phenoxyacetamido-2-oxoacetidine (A) and 0.287 g of (3S, 4S) -4-methoxy-3-phenoxyacetamido-2-oxoacetidine (B).

(A) KBr IR 0 cm -1; 3280, 3175, 1760, 1663 max PMR (acetone-dg, ppm); 3.35 (s, CH 3), 4.51 (s, CH 2 -), 4.68 (dd, J = 1.5, 9H2, C3-H), 4.98 (d, J = 1.5 Hz, C4-H), 6.83-7.43 (m, arom.H), 7.80-8.30 (m, NH) B) KBr IR 0 cm-1; 3320, 3200, 1763, 1658 max.

Comparative Example 13 Anti-isomer and syn-isomer of (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine

To a solution of 1 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine in 30 ml of tetrahydrofuran is added 500 mg of palladium on carbon, and the mixture is stirred under a stream of hydrogen for one hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to about 10 ml.

On the other hand, 2 g of the syn isomer of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid are added to 20 ml of methylene chloride, and 0.87 g of triethylamine and 1.5 g of phosphorus pentachloride are added under ice-cooling. The mixture is stirred for 5 minutes under ice-cooling, then further stirred at room temperature for 30 minutes, then concentrated under reduced pressure, the residue is washed with hexane, 10 ml of THF are added and the insoluble components are removed by filtration, the filtrate is added under ice-cooling and added dropwise to the above solution. and 3 ml of propylene oxide The solvent is removed by distillation under reduced pressure and the remaining ethyl acetate solution is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. g of (3S, 4S) -4-aceto xis-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine anti-isomer and 0.20 g of the eyn-isomer and 0.30 g of a mixture of both isomers.

(Syn-isomer) KBr IR>) cm -1; 3270, 1770, 740, 1720, 1665, 1545 max PMR (DMSO-d 6, ppm); 2.17 (s, CH 3), 4.00 (s, CH 3) (4.40 ( s, -CH 2 -), 4.90 (dd, J = 2.8Hz, C 3 -H), 5.93 (d, J = 2Hz, C 4 -H), 7.52 (s, y »), 9.30 (s, NH), 9.43 (d, J = 8Hz, NH), 12.87 (s, NH), (Anti-isomer) KBr IR 0 cm -1; 3250, 1770, 1750 (olake), 1665, 1540 max PMR (DMSO-d 6, ppm 2.13 (s, CH3), 4.07 (s, CH3), 4.40 (s, -CH2-), 4.90 (dd, J = 2.9Hz, C3-H), 5.88 (d, J = 2Hz, C4 -H), 8.02 (s, 9.30 (d, J = 9Hz, NH), 9.35 (s, NH), 12.77 (s, NH)

Comparative Example 14 (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylsulfonyl-2-oxoazetidine

Applying the procedure of Comparative Example 13 but using 0.298 g of (3R, 4R) -3-benzyloxycarboxamido-4-methylsulfonyl-2-oxoazetidine and 0.638 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) - 2-phenylacetic acid, 0.114 g of (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4 methylsulfonyl-2-oxoazetidine.

i KBr IR ^ cm-1; 3270, 1778, 1700, 1668, 1500 max 43 79528 PMR (DMSO-d 6, ppm); 1.09 (t, J = 7Hz, CH3), 2.27 (s, CH3), 3.40 (q, J = 7Hz / -CH2-), 3.44-3.66 (m, -CH2-), 3.78-4.02 (m, -CH2- ), 4.94 (d, J = 5Hz, C4-H), 5.61 (dd, J = 5.9Hz, C3-H), _CH- 5.72 (d, J = 7Hz, ·), 7.25-7.54 (m, aroma .H), 9.08 (d, J = 9Hz, NH), 9.33 (S, NH), 9.85 (d, J = 7Hz, NH).

Comparative Example 15 Anti- and syn-isomer of (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylsulfonyl-2-oxoazetidine

Applying the procedure of Comparative Example 13 but using 0.298 g of (3R, 4R) -3-benzyloxycarboxamido-4-methylsulfonyl-2-oxoazetidine and 0.555 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid the syn isomer of the acid gives 0.205 g of (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylsulfonyl-2-oxoacetidine.

(Syn isomer) KBr IR i> cm -1; 3370, 3270, 1790, 1680, 1540 max PMR (DMSO-d 6 / ppm); 3.00 (s, CH 3), 3.93 (s, CH 3), 4.33 (s, -CH2-), 4.93 (d, J = 5Hz, C4-H), 5.57 (dd, J = 5.9Hz, C3-H), 7.53 (s,

V

I), 8.30 (d, J = 9Hz, NH), 9.40 (S, NH), 12.73 (s, NH) (Anti-isomer) KBr IR 0 cm -1; 3380, 3250, 1790, 1680, 1540 max PMR (DMSO-d 6, ppm), 2.97 (s, CH 3), 3.95 (s, CH 3), 4.27 (S, -CH 2 -),

5.07 (d, J = 5Hz, C4-H), 5.75 (dd, J = 5.9Hz, C3-H), 7.99 S H

(s, Y), 8.67 (d, J = 9 Hz, NH), 9.40 (s, NH), 12.77 (8, NH) Comparative Example 16 3S4S) -4-Acetoxy-3- (2- (2-chloroacetamidothiazole-4 -yl) -2-isopropoxyiminoacetamido) -2-oxoazetidine syn isomer

To a solution of 1.12 g of (3S, 4S) -4-acetoxy-3-benzyl-14,79528 oxycarboxamido-2-oxoazetidine in 30 ml of THF is added 400 mg of palladium on carbon and the mixture is stirred under a stream of hydrogen gas. for an hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to 5 ml.

On the other hand, to a solution of 0.410 g of DMF in 10 ml of methylene chloride is added 0.475 g of diphosgene at -10 ° C, and the mixture is stirred at room temperature for 15 minutes. A solution of 1.23 g of the syn-isomer of 2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetic acid and 0.530 g of triethylamine in 15 ml of methylene chloride at -60 to -50 ° C is added dropwise and the mixture is stirred at -40 to about -30 ° C for 1.5 hours. 0.490 g of triethylamine are then added at -60 to about -50 [deg.] C., and the THF 'solution prepared above is also added. The mixture is allowed to stand at room temperature for one hour, after which the solvent is removed by distillation under reduced pressure. The residual ethyl acetate solution is washed with water and concentrated under reduced pressure. The residue is purified on a silica gel column (2: 1 solution of ethyl acetate and n-hexane as eluent) to give 1.23 g of (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxy -iminoacetamido) -2-oxoazetidine syn-isomer KBr IR 0 cm-1; 3280, 1762, 1670, 1226 max PMR (DMSO-d 6, ppm); 1.25 (d, CH 3), 2.13 (s, CH 3), 4.37 (s, -CH- -CH 2 -), 4.30-4.67 (m, 1), 4.87 (d, J = 1.8 Hz, C 3 -H ), S> J * 5.89 (d, J = 1Hz, C4-H), 7.43 (s, | f), 9.29 (s, NH), 9.32 1 (d, J * 8Hz, NH), 13.0 5 (s , NH).

Comparative Example 17 (3S, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methoxy-2-oxoazetidine 5,79528

To a solution of 0.300 g of (3S, 4S) -3-benzyloxycarboxamido-4-methoxy-2-oxoazetidine in 10 ml of THF is added 150 mg of palladium on carbon, and the mixture is stirred under a stream of hydrogen gas for one hour. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to 3 ml.

On the other hand, to a solution of 0.383 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid in 5 ml of DMF is added 0.215 g of N-hydroxy-5- norborene-2,3-dicarboximide followed by 0.248 g of DCC and the mixture is stirred at room temperature for 3 hours. To this mixture is added the concentrated solution prepared above, followed by. . The mixture is stirred for 17 hours. Insoluble components are removed by filtration, and the filtrate is concentrated under reduced pressure. Ethyl acetate and THF are added to the residue. The mixture is washed with 5% aqueous sodium bicarbonate solution and water, respectively, and dried over magnesium sulfate. Concentrate under reduced pressure to give 0.250 g of (3S, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methoxy- 2-oxo-azetidine.

KBr IR 0 cm-1; 3275, 1770, 1710, 1670, 1508 and max PMR (DMSO-d 6, ppm); 1.08 (t, J = 7Hz, CH3), 3.23 (s, CH3), 3.80 (q, J = 7Hz, -CH2-), 3.43-3.66 (m, -CH2-), 3.80-4.07 (m, -CH2) -), 4.41 (dd, J = 1.8Hz, C3-H), 4.67 (d, J = 1Hz, C4-H), 5.42 (d, -CH- J = 7Hz, *), 7.35 (s, aroma .H), 8.98 (s, NH), 9.09 (d, J = 8Hz, NH), 9.78 (d, J = 7Hz, NH).

Comparative Example 18 (3S, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2-phenylacetamido) -4-methoxy-2-oxoazetidine

Applying the procedure of Comparative Example 17, but using 0.300 g of (3S, 4R) -3-benzyloxycarboxamido-4-46,79528 methoxy-2-oxoazetidine and 0.383 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido ) -2-Phenylacetic acid 0.260 g of (3S, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -2-phenylacetamido) -4- methoxy-2-oxoazetidine.

\ KBr 1 IR V cm-1; 3275, 1770, 1700, 1665, 1500 max PMR (DMSO-d 6, ppm); 1.07 (t, J = 7Hz, CH3), 2.85 (s, CH3), 3.38 (q, J = 7Hz, -CH2-), 3.40-3.67 (m, -CH2-), 3.73-4.03 (m, -CH2) -), 4.80 (d, J = 4Hz, C4-H), 5.07 (dd, J = 4.9Hz, C3-H), 5.58 (d, -CH- J = 7Hz, I), 7.33 (s, aroma .H), 8.95 (s, NH), 9.07 (d, J = 9Hz, NH), 9.84 (d, J = 7Hz, NH).

Comparative Example 19 (3S, 4S) -4-Acetoxy- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoazetidine

Applying the procedure of Example 17 but using 2.8 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine and 3.2 g of D-2- (4-ethyl-2,3-dioxo -1-Piperazinecarboxamido) -2-phenylacetic acid gives 1.0 g of (3S, 4S) -4-acetoxy- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) - 2-oxoazetidine.

KBr "IR 1) cm-1; 1785, 1715, 1675, 1510 max PMR (DMSO-d 6, ppm); 1.10 (t, J = 6Hz, CH 3), 2.05 (s, CH 3), 3.5 2 (m, - CH2-), 3.90 (m, -CH2-), 4.60 (dd, J = 2.8Hz, -CH- C3-H), 5.48 (d, J = 6Hz, 1), 5.72 (d, J = 2Hz, C4-H), 7.40 (s, arom.H), 9.06 (d, J = 8Hz, NH), 9.16 (broad s, NH), 9.78 (d, J = 6Hz, NH) 47,79528

Comparative Example 20 (35.45) -4-Acetoxy-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine syn isomer

To a solution of 500 mg of the syn-isomer of (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 10 ml DMF is added 0.245 g of sodium monomethyldithiocarbamate and the mixture is stirred at room temperature for one hour. The solvent is removed by distillation under reduced pressure, the residue is washed three times with ethyl acetate, ethanol is added, and insoluble components are removed by filtration. The filtrate is concentrated under reduced pressure. The residue is purified on a silica gel column (eluent: ethyl acetate / CHCl 3 and CH 3 OH 2: 2: 1) to give 0.270 g of (3S, 4S) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2 -methoxyimino-acetamido) -2-oxoazetidine syn isomer.

KBr * IR <) cm -1; 3280, 1770, 1740, 1720, 1660, 1520, 1215, max 1035 PMR (DMSO-d 6, ppm); 2.12 (s, CH3), 3.70 (s, CH3), 4.78 (dd, J = 1.8Hz, C3-H), 5.88 (d, J = 1Hz, C4-H), 6.85 (s,), 7.20 ( s, NH 2), 9.30 (s, NH), 9.33 (d, J = 8Hz, NH).

Comparative Example 21 Cis-trans mixture of the syn-isomer of (2S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido)) - 2-oxoazetidine

To a solution of 0.380 g of (35,45) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 1 ml of DMF is added a solution of 0.079 g of sodium azide in 1 ml of water and the mixture is stirred at room temperature for 15 hours.

Ethyl acetate and saturated aqueous sodium chloride solution are added, after which the organic layer is separated and washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified on a silica gel column (eluent: ethyl acetate, CHCl 3: CH 3 OH 4: 4: 1) to give 0.201 g of (3S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido ) A cis-trans mixture of the syn-isomer of -2-oxoazetidine. v KBr IR v cm-1; 3275, 2100, 1765, 1665, 1540 max

Comparative Example 22 (35.45) -4-Azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoacetidine

Applying the procedure of Comparative Example 21 but using 2.2 g of (3S, 4S) -4-acetoxy-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) - 2-Oxoazetidine and 0.36 g of sodium azide give 1.6 g of (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2 phenylacetamido) -2-oxoazetidine.

KB r IR 1 cm -1; 2100, 1780, 1705, 1670, 1505: max

Comparative Example 23

In the same manner as in Comparative Example 7, 0.415 g of (3S, 45) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylthio-2-oxoazetidine is obtained.

KB Γ IR d cm -1; 1765, 1705, 1670, 1510 max PMR (DMSO-d 6, ppm); 1.09 (t, J = 6Hz, CH 3), 2.06 (s, SCH 3), 3.32 (q, J = 6Hz , -CH 2 -), 3.64 (m, -CH 2 -), 3.90 (m, -CH 2 -), 4.68 (dd, J = 2.8, C 3 -H), 5.46 (d, J = 6Hz, '-CH - *), 5.72 (d, J = 2Hz, C4-H), 7.38 (broad s, arom.H), 8.72 (broad s, NH), 9.18 (d, J = 8Hz, NH), 9.78 (d, J = 49 79528 6Hz, NH)

Comparative Example 24 (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylsulfinyl-2-oxoazetidine Treat 0.90 g of methyl (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylthio-1- (isopropylidene) acetate ozone in methylene chloride with a reducing agent followed by a base in methanol. The reaction gives 0.42 g of (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazine-1-carboxamido) -2-phenylacetamido) -4-methylsulfinyl -2-oxoazetidine.

KBx "IR ^ cm" 1; 1775, 1710, 1675, 1510 max

O

PMR (DMSO-d 6, ppm); 1. 10 (t, J = 6Hz, CH 3), 2.08 (s,), 3.41 (q, J = 6Hz, -CH 2 -), 3.56 (m, -CH 2 -), 3.90 (m, -CH 2 -), 4.64 (d, J = 4H2, C4-H), 5.46 (dd, J = 4.8Hz, C3-H), -CH- 5.64 (d, J = 6Hz, *), 7.4 (broad s, arom.H ), 9.06 (d, J = 8Hz, NH), 9.18 (broad s, NH), 9.93 (d, J = 6Hz, NH).

Comparative Example 25 (3S, 4S) -4-Acetoxy-3-benzyloxycarboxamido-tert-butyldimethylsilyl-2-oxoazetidine 1 ____ To a solution of 2.78 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2 -oxoazetidine in 15 ml of DMF, 1.11 g of triethylamine and 1.66 g of t-butyldimethylchlorosilane are added under ice-cooling, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into ice water and ethyl acetate, and the organic layer is separated, washed with water and dried over magnesium sulfate. Concentrate under reduced pressure, then purify the residue on a silica gel column (1: 2 mixture of ethyl acetate and n-hexane as eluent) to give 2.98 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-1-t -butyldimethylsilyl-2-oksoatseti-uracil.

. pure IR ν cm -1; 3330, 2950, 2930, 1750, 1720, 1520, 1250, 1 max 1152, 1045 PMR (CDCl 3, ppm); 0.23 (s, CH 3), 0.97 (s, t-Bu), 2.05 (s, CH 3), 4.40 (dd, J = 1.8 Hz, C 3 -H), 5.05 (s, -CH 2 -), 5.90 (d, J = ΘΗζ, ΝΗ), 6.04 (d, J = 1 Hz, C 4 -H), 7.23 (s, arom.H)

Comparative Example 26 (3S, 4S) -4-acetoxy-3-amino-1-t-butyldimethylsilyl-2-oxoazetidine

To 15 ml of a THF solution containing 0.62 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-1-butyldimethylsilyl-2-oxoazetidine, 0.3 g of palladium on carbon are added and the mixture is stirred under a stream of hydrogen gas for one hour. I drive. 0.2 g of palladium on carbon are added, after which the mixture is stirred for a further 30 minutes and the catalyst is removed by filtration. Concentrate under reduced pressure to give 0.387 g of (3S, 4S) -4-acetoxy-3-amino-1-t-butyl-dimethylsilyl-2-oxoazetidine.

. pure IR V cm-1; 3375, 3325, 2950, 2930, 1750, 1230 max PMR (CDCl 3, ppm); 0.24 (s, CH3), 0.26 (s, CH3), 0.97 (s, t-Bu), 1.81 (broad s, NH2), 2.13 (s, CH3), 4.16 (d, J = 1Hz, C3-H) , 5.69 (d, J = 1 Hz, C4-H).

Comparative Example 27 (3S, 4S) -4-acetoxy-1-t-butyldimethylsilyl-3-phenylacetamido-2-oxoazetidine

To a solution of 0.387 g of (3S, 4S) -4-acetoxy-3-amino-79528 1-t-butyldimethylsilyl-2-oxoazetidine in 20 ml of THF is added 0.24 g of triethylamine under ice-cooling, and then dropwise a solution of 0.32 g of phenylacetyl chloride in THF. The mixture is stirred under ice-cooling for 1 hour, the insoluble components are removed by filtration and the filtrate is concentrated under reduced pressure · The residue is purified on a silica gel column (eluent: 1: 2 ethyl acetate / n-hexane) to give 0.511 g of (3S, 4S) -4-acetoxy-lt- butyl-dimethylsilyl-3-phenylacetamido-2-oxo-azetidine. v pure IR ν cm -1; 3290, 2950, 2930, 1750, 1658, 1525, 1252, max 1235, 1042 PMR (CDCl 3, ppm); 0.24 (s, CH 3), 0.97 (S, t-Bu), 2.04 (s, CH 3), 3.55 (s, -CH 2 -), 4.36 (dd, J = 1.8 Hz, C 3 -H), 6.06 (d, J = 1 Hz, C 4 -H), 6.57 (broad s, NH), 7.19 (s, arom.H).

Comparative Example 28 (3S, 4S) -4-Acetoxy-3- (2-bromo-2-phenylacetamido) -1-t-butyldimethylsilyl-2-oxoazetidine

Applying the procedure of Comparative Example 16, but using 0.385 g of (3S, 4S) -4-acetoxy-3-amino-tert-butyl-dimethylsilyl-2-oxoazetidine and 0.384 g of 2-bromo-2-phenylacetic acid, 0.40 g (3S , 4S) -4-acetoxy-3- (2-bromo-2-phenylacetamido) LT-butyldimethylsilyl-2-oxoazetidine.

. pure IR ν cm -1; 3305, 2950, 2930, 1750, 1675, 1515, 1222 max PMR (CDCl 3, ppm); 0.23, 0.30 (each s, CH 3), 1.00 (s, t-Bu), -CH - 2.13 (s, CH 3), 4.70 (m, C 3 -H), 5.51 (broad s, 1), 6.23, 6.27 (each d, J = 2 Hz, C 4 -H), 7.47 (s, arom.H).

Comparative Example 29 (3S, 4S) -4-Acetoxy-3- (2- (2-oxoimidazolidin-1-yl-carboxamido-2- (benzothiophen-3-yl) -acetamido) -2-oxoazetidine 52,79528

Applying the procedure of Comparative Example 17, but using 0.84 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine and 1.18 g of 2- (2-oxoimidazolidin-1-yl) carboxamido) - (benzothio-phen-3-yl) -acetic acid, 0.994 g of (3S, 4S) -4-acetoxy-3- (2- (2-oxoimidazolidin-1-yl) carboxamido-2- (benzothiophen-3-yl) -ase--acetamido) -2-oxoazetidine.

IR>) cm -1; 3290, 1785, 1720, 1675, 1520, 1270, 1228 max PMR (DMSO-d 6, ppm); 2.07 (s, CH 3), 3.10-3.53 (m, -CH 2 -), 3.53- 3.90 (m, -CH 2 -), 4.63, 4.65 (each dd, J = 1.8 Hz, C 3 -H), 5.77-5.81 (each d, J = 1 Hz, C 4 -H), 5.87 (d, J = 8Hz, -CH-), 7.30-8.15 (m, arom.H), 7.59 (s, -NH-), f 8.90-9.20 (m, NH), 9.20 (s, NH).

Comparative Example 30 (3R, 4R) -4- (Benzothiazol-2-yl) -dithio-3-phenoxy-acetamido-2-oxo-azetidine By treating 3 g of methyl- (3R, 4R) -4- (benzothiazol-2-yl) - Dithio-3-phenoxyacetamido-2-oxoazetidine-1- (0C-isopropylidene) acetate as described in Comparative Example 1 1.74 g of (3R, 4R) -4- (benzothiazol-2-yl) -dithio-3- phenoxy-acetamido-2-oxoazetidine.

KBr IR 1 cm -1; 3320, 1800, 1770, 1660 max PMR (DMSO-d 6, ppm); 4.68 (s, -CH 2 -), 5.38 (m, C 3 -H, C 4 -H), 6.90-8.08 ( m, arom.H), 9.10 (d, J = 5 Hz, NH), 9.17 (s, NH).

Comparative Example 31 (3S) -4-Azido-3- (2- (benzothiophen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido) acetamido) -2-oxoacetidine

To a solution of 0.446 g of (3S, 4S) -4-acetoxy-3- (2-benzothio, phen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido) acetamido) -2 -oxoazetidine in 4 ml of DMF is added under ice-cooling 53 79528 to a solution of 0.085 g of sodium azide in 2 ml of hydrogen. The mixture is stirred for 15 hours at room temperature, then water is added and the precipitate formed is collected by filtration to give 0.321 g of (3S) -4-azido-3- (2- (benzothiophen-3-yl) -2- (2-oxoimidazolidin-1 -yl-carboxylic-amido) acetamido) -2-oxoazetidine.

KB r IR 0 cm -1; 3270, 2110, 1775, 1720, 1670, 1522, 1268 max

Comparative Example 32 (3S) -4-Azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-. Methoxyiminoacetamido) -2-oxoazetidine

To a solution of 3.08 g of (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 3 mL of DMF A solution of 0.061 g of sodium azide in 2 ml of water is added under ice-cooling. The mixture is stirred for 18 hours at room temperature, then water is added and the precipitate formed is collected by filtration to give 0.216 g of (3S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxy). iminoacetamido) -2-oxoate-1. setidiinia.

- * KBr. · !! IR>) cm-1; 3270, 2110, 1768, 1662, 1540, 1275 max PMR (DMSO-d 6, ppm); 1.25 (d, J = 6Hz, CH3), 4.17 (s, trans -CH2-), -CH- 4.36 (s, cis -CH2-), 4.25-4.50 (m, *), 4.75 (dd, J = 2,

8H2, trans C3-H), 5. 11 (d, J = 2Hz, trans C4-H), 7.39 (s, cis H H

), 7.42 (s, trans Y), 9.00 (s, cis NH), 9.05 (s, trans NH), 9.27 (d, J = 8Hz, trans NH), 9.43 (d, J = 8Hz, cis NH), 12.72 (s, trans NH), 12.84 (s, cisNH).

Comparative Example 33 (3S, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy-2-oxoazetidine 79528

To a solution of 0.532 g of (3S, 4R) -3-benzyloxycarboxamido-4-phenylacetoxy-2-oxoazetidine in 15 ml of THF is added 0.35 g of palladium on carbon, followed by stirring for 1 hour under a stream of hydrogen gas. The catalyst is removed by filtration and the filtrate is concentrated to a volume of 7 ml.

On the other hand, 0.11 ml of diphosgene is added to 0.154 g of DMF dissolved in 8 ml of methylene chloride at -10 ° C. The mixture is stirred for 20 minutes at room temperature, then 7 ml of a methylene chloride solution containing 0.46 g of 2- (2-chloroacetamido-thiazol-4-yl) -2-methoxy are added dropwise at -60 n -70 ° C. -iminoacetic acid and 0.213 mg of triethylamine. The mixture is then stirred for 1.5 hours at -25 n -20 ° C, then cooled to -70 ° C, and 0.213 g of triethylamine, the THF solution prepared above and 2 ml of propylene oxide are added to the mixture. The temperature of the mixture is raised to room temperature within one hour with stirring, then concentrated under reduced pressure. THF is added to the residue, and insoluble components are removed by filtration. The filtrate is concentrated under reduced pressure, followed by the addition of ethyl acetate. The formed crystals are collected by filtration to give 0.236 g of (3S, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy-2-oxoazetidine.

KBr: IR 0 cm -1; 3260, 1770, 1735, 1670, 1545, 1245, 1042 max PMR (DMSO-d 6, ppm); 3.68 (s, -CH 2 -), 3.90 (s, OCH 3), 4.37 (s , -CH 2 -), 5.45 (dd, J = 4.9Hz, C 3 -H), 6.04 (d, J = 4Hz,

B

C4-H), 7.28 (s, arom.H), 7.36 (s, Ύ>, 9.17 (., NH), 9.41 (d, J = 9Hz, NH).

Comparative Example 34 (3R, 4R) -4-Acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoazetidine 55,79528

To a solution of 0.815 g of pivaloyloxymethyl- (3R, 4R) -4-a, cetylthio-3- (4-ethyl-2,3-dioxo-1-piperazine-carboxamido) -2-phenylacetamido) -2 -oxoazetidine 1- (<* -isopropylidene) acetate in 60 ml of methylene chloride, ozone is bubbled in for 14 minutes at -70 ° C, followed by nitrogen gas for 50 minutes. The solution is washed with 5% aqueous sodium bisulfite solution and water, respectively, then dried over magnesium sulfate and concentrated under reduced pressure. To the residue are added 100 ml of methanol and 2 ml of water. The mixture is stirred for 15 hours and the solvent is removed by distillation. The residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent). There are thus obtained::: 0.468 g of (3R, 4R) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoacetidine .

S KBr IR ν cm -1; 3275, 1775, 1708, 1670, 1502, 1180 max PMR (DMSO-d 6, ppm); 1.08 (t, J = 7Hz, CH 3), 2.07 (6, CH 3), 3.40 (q , J = 7Hz, -CH 2 -), 3.40-3.66 (m, -CH 2 -), 3.80-4.03 (m, -CH 2 -), 5.30-5.50 (m, C 3 -H, C 4 -H), 5.53 (d , J = 7Hz,

A: -CH

1), 7.25-7.56 (m, arom.H), 8.82 (s, NH), 9.29 (m, NH), 9.87 (d, J = 7Hz, NH)

Comparative Example 35 (3S, 4S) -4-Acetoxy-3-tritylamino-2-oxoazetidine

To a solution of 10 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoathetidine in 200 ml of THF is added 2.5 g of palladium on carbon, followed by stirring for 1 hour under a stream of hydrogen gas. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to a volume of 50 ml. 50 ml of methylene chloride are added to the concentrate under ice-cooling. A solution of 10.52 g of trityl chloride in 100 ml of methylene chloride is added dropwise to the mixture, followed by stirring for 3 hours at room temperature. The reaction mixture is concentrated under reduced pressure. Ether is added to the residue. The formed crystals are collected by filtration to give 13.1 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-oxoazetidine.

KBr IR >> cm -1 1320, 1775, 1735, 1230, 1030 max PMR '(CDCl 3, ppm); 1.05 (s, CH 3), 2.90 (broad s, NH), 4.27 (d, J = 1Hz, C 3 - H), 4.87 (d, j = 1Hz, C4-H), 6.58 (s, NH), 7.27-7.77 (m, arom.H)

Comparative Example 36 (3R, 4R) -4-Acetylthio-3-tritylamino-2-oxoazetidine

To a solution of 0.7 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-oxoazetidine in 10 ml of methanol is added a solution of 0.25 g of potassium thioacetate in 2 ml of water. The mixture is stirred for 30 minutes at 55-60 ° C. The methanol is removed by distillation under reduced pressure. Ethyl acetate is added to the residue, followed by washing with water, drying and concentration under reduced pressure. The residue is purified on a silica gel column (1: 1 mixture of acetate and n-hexane as eluent) to give 0.195 g of (3R, 4R) -4-acetylthio-3-tritylamino-2-oxoazetidine.

KBr IR ^ cm-1; 3290, 1775, 1765, 1690, 1665 max PMR (CDCl 3, ppm); 2.30 (s, CH 3), 3.05 (broad s, NH), 4.77 (m, C 3 -H), 5.13 (d, J = 5 Hz, C 4 -H), 6.57 (s, NH), 7.20-7.73 (m. arom.-H)

In addition, 0.417 g of the corresponding (3R, 4S) -isomer KBr IR 0 cm-1 is obtained; 3320, 1760, 1685 max PMR (CDCl 3, ppm); 2.15 (s, CH3), 3.05 (s, NH), 4.23 (d, J = 2Hz), C3-H), 4.66 (d, J = 2Hz, C4-H), 6.77 (s, NH), 7.27- 7.77 (m, arom.-H).

57 79528

Comparative Example 37 (3S, 4S) -4-Acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoazetidine

To a solution of 0.819 g of (3R, 4S) -4-acetylthio-3-tritylamino-2-oxoazetidine in 6 ml of acetone is added 0.453 g of p-toluenesulfonic acid monohydrate under ice-cooling. The reaction is allowed to proceed for 15 hours. The acetone is removed by distillation under reduced pressure. The residue is washed with ether and then dissolved in 20 ml of methylene chloride. To the solution is added 0.174 g of pyridine at -10 ° C, followed by stirring for 5 minutes.

: · On the other hand, 0.24 g of trimethylchlorosilane are added to a solution of 0.703 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid in 20 ml of methylene chloride. and 0.223 g of triethylamine. The mixture is stirred for 40 minutes at room temperature, then cooled to -25 to -20 ° C. 0.161 g of DMF and 0.13 g of diphosgene are added to the solution, and the mixture is stirred for 2 hours, then cooled to -70 ° C. 0.223 g of triethylamine is added to the mixture, followed by the suspension prepared above and 2 ml of propylene oxide. The temperature of the mixture is raised to room temperature within 1.5 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified on a silica gel column (eluent: 1: 1 mixture of ethyl acetate and n-hexane) to give 0.567 g of (3S, 4S) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo- 1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoacetidine.

KBx * IR ύ cm-1; 3275, 1775, 1763, 1670, 1500, 1180 max PMR (DMSO-d 6, ppm); 1.09 (t, J = 7Hz, CH3), 2.34 (s, CH3), 3.41 (q, J = 7Hz, -CH2-), 3.40-3.70 (m, -CH2-), 3.80-4.05 (m, -CH2) -), 4.77 (dd, J = 2.9Hz, C3-H), 5.10 (d, J = 2Hz, C4-H), 7.4 0 (s, arom.H), 8.93 (s, NH), 9.26 ( d, J = 9Hz, NH), 9.84 (d, J = 8Hz, NH) se 79528

Comparative Example 38 (3R, 4R) -4-Acetylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine

To a solution of 0.828 g of (3R, 4R) -4-acetylthio-3-tritylamino-2-oxoazetidine in 5 ml of acetone is added 0.45 g of p-toluenesulfonic acid monohydrate under ice-cooling, and stirred for 1 hour at room temperature. The acetone is removed by distillation under reduced pressure, and the residue is washed with ether and then dissolved in 20 ml of methylene chloride. 0.211 g of pyridine are added to the solution at -10 ° C, followed by stirring for 5 minutes.

On the other hand, to a solution of 0.18 g of DMF in 5 ml of methylene chloride is added 0.148 ml of diphosgene at -10 ° C, and the mixture is stirred for 3 minutes at room temperature. The reaction mixture is cooled to -70 ° C and 15 ml of a methylene chloride solution containing 0.627 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid and 0.25 g of triethylamine are added dropwise . The whole mixture, cooled to -70 ° C, is stirred for 1.5 hours at -25 to -20 ° C. To the thus cooled mixture is added 0.25 g of triethylamine, followed by the suspension prepared above and an additional 2 ml of propylene oxide, after which the temperature is allowed to rise to room temperature over one hour with stirring. The reaction mixture is concentrated under reduced pressure. The residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 0.296 g of (3R, 4R) -4-acetylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxy -iminoasetamido) -2-oxoazetidine.

KBx * IRύ cm -1; 3240, 1770, 1755, 1655, 1530 i max PMR (DMSO-d 6, ppm); 1.87 (s, CH 3), 3.95 (s, OCH 3), 4.38 (s, -CH 2 -), 5.36 (dd, J = 5.8 (C3-H), 5.68 (d, J = 5Hz, C4-H),

S H

7.56 (s, Y), 8.72 (d, J = 8Hz, NH), 8.99 (s, NH), 12.87 (s, NH) 59,79528

Comparative Example 39 (3R, 4S) -4-Acetylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine Using 0.805 g of (3R, 4S) -4-acetylthio- 3-tritylamino-2-oxoazetidine, 0.437 g of p-toluenesulfonic acid monohydrate, 0.19 g of pyridine and 0.175 g of DMF, 0.144 ml of diphosgene, 0.61 g of 2- (2-chloroacetamidothiazol-4-yl) 2-Methoxyiminoacetic acid, 0.243 g of triethylamine and 2 ml of propylene oxide are obtained by applying the method of Comparative Example 38 to 0.548 g of (3R, 4S) -4-acetylthio-3- (2- (2-chloroacetamidothiazol-4-yl) ) -2-methoxyiminoacetamido) -2- oxoazetidine.

... * KBr IR >> cm -1; 3260, 1752, 1690, 1662, 1525 ____: max PMR (DMSO-d 6, ppm); 2.40 (s, CH 3), 3.90 (s, CH 3), 4.34 (s , -CH 2 -), 4.93 (dd, J = 2.8Hz, C 3 -H), 5.21 (d, J = 2Hz, C 4 -H), 7.42 (s, Y), 8.97 (S, NH), 9.40 ( d, J = 8Hz, NH), 12.93 (8, NH)

Comparative Example 40 (3R, 4R) - (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylsulfonyl-2-oxoazetidine

To a solution of 0.48 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid in 10 ml of methylene chloride are added 0.18 g of trimethylchlorosilane and 0.17 g of triethylamine. The mixture is stirred for 30 minutes at room temperature, then cooled to -25 to -20 ° C and 0.12 g of DMF and 0.10 ml of diphosgene are added. The mixture is stirred for 2 hours, then cooled to -70 ° C and 0.17 g of triethylamine, a solution of 0.205 g of (3R, 4R) -3-amino-4-methylsulphonyl-2-oxoazetidine in 3 ml of DMA, are added. and 2 ml of propylene oxide. The temperature of the reaction mixture is raised to room temperature within 1.5 hours, after which 60,79528 the reaction mixture is concentrated under reduced pressure. The residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 0.418 g of (3R, 4R) - (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2 phenylacetamido) -4-methylsulfonyl-2-oxo-azetidine. According to the IR and PMR spectra, this product is the same product prepared in Comparative Example 14.

Comparative Example 41 (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylsulfonyl-2-oxoazetidine

To a solution of 0.122 g of DMF in 5 ml of methylene chloride is added 0.10 ml of diphosgene at -10 ° C. The mixture is stirred for 30 minutes at room temperature, then cooled to -70 [deg.] C. and 10 ml of a methylene chloride solution containing 0.427 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid and 0 ml of methylene chloride are added dropwise. 17 g of triethylamine. The mixture is stirred for 2 hours at -25 to -20 ° C, cooled to -70 ° C and 0.17 g of triethylamine, a solution of 0.229 g of (3R, 4R) -3-amino, is added in turn. -4-methylsulfonyl-2-oxoazetidine in 3 ml of DMA, and 2 ml of propylene oxide. The mixture is allowed to warm to room temperature within 1.5 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 0.415 g of (3R, 4R) -3- (2- (2-chloroacetamide, thiazol-4-yl) -2-methoxyiminoacetamido) -4-methylsulfonyl-2-oxoazetidine. This corresponds to the syn-isomer of the compound obtained in Comparative Example 15 according to the IR and PMR spectra.

Comparative Example 42 (3S, 4R) -isomer of (3S, 4R) -4-methoxy-3-tritylamino-2-oxoazetidine.1795528

To a solution of 3 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-azetidine in 30 ml of methanol is added 1.7 g of zinc acetate, and the mixture is boiled for 30 minutes under reflux. The reaction mixture is concentrated under reduced pressure, followed by the addition of ethyl acetate. The insoluble components formed are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 0.912 g of (3S, 4R) -4-methoxy-3-tritylamino-2-oxoacetidine.

KBr IR 0 cm -1; 3270, 3210, 1772, 1725, 1097 max PMR (CDCl 3, ppm); 2.98 (s, OCH 3), 3.01 (d, J = 9Hz, NH), 3.88 (d, J = 4Hz, C4-H), 4.08 (dd, J = 4.9Hz, C3-H), 6.60-8.05 (m, arom.H)

In addition, the (3S, 4S) -isomer KBr IR 0 cm-1 is obtained; 3280, 1760, 1100. . max PMR '(CDCl 3, ppm); 2.81 (s, OCH 3), 3.27 (s, NH), 3.95 (s, C 3 -H, C 4 -H), 6.70-8.00 (m, arom.H)

Comparative Example 43 (3R, 4S) -4-Methylthio-3- (2- (2-methylthioacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -2-oxo-azetidine

To a solution of 0.7 g of (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine isomer in 4 ml of DMF, 1.3 ml of a 15% aqueous solution of sodium methyl sulfide are added under ice-cooling, and the mixture is stirred for 2 hours at room temperature. Ethyl acetate and water are added to the mixture, and the organic layer is separated and washed with water and concentrated. Residue 1 is purified on a silica gel column (eluent CHCl3, 79528 6 2

AcOEt and CH 3 OH 7: 7: 1) to give 0.377 g of (3R, 4S) -4-methylthio-3- (2- (2-methylthioacetamido-thiazol-4-yl) -2-methoxy- iminoacetamido) -2-oxo-azetidine.

KB x IR 1 cm -1; 3240, 3190, 1752, 1655, 1548, 1290, 1042 max PMR (DMSO-d 6, ppm); 2.17 (s, SCH 3), 3.37 (s, -CH 2 -), 3.90 (s, OCH 3), 4.67 (d, J = 2Hz, C 4 -H), 4.71 (dd, J = 2.8Hz, C 3 -H), 7.36 (s,), 8.77 (s, NH), 9.3 Δ (d, J = 8Hz, NH), 12.56 (s,, NH)

Comparative Example 44 (3S, 4R) -4-Azido-3-tritylamino-2-oxoazetidine and the (3S, 4S) -isomer

To a solution of 3.0 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-oxoazetidine in 50 ml of methanol is added, under ice-cooling, a solution of 0.65 g of sodium azide in 5 ml. • water, followed by stirring for 2 hours at 40-50 ° C.

The solvent is removed by distillation under reduced pressure. Ethyl acetate is added to the residue, and the organic layer is separated, washed with water and concentrated. The residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 1.01 g of (3S, 4R) -4-azido-3-tritylamino-2-oxoacetidine.

KB x IR ν cm -1; 3315, 2102, 1775, 1765, 1255 max PMR (CDCl 3, ppm); 2.82 (d, J = 10 Hz, NH), 4.07-4.40 (m, C 3 -H, C 4 -H ), 6.48 (s, NH), 6.95-7.50 (m, arom.H)

In addition, 1.52 g of the (3S, 4S) -isomer KBE IR ^ cm-1 are obtained; 3315, 2098, 1765, 1245 max PMR (CDCl 3, ppm); 2.93 (s, NH), 3.98 (s, C3-H, C4-H), 6.92 (s, NH), 7.00-7.57 (m.arom.H)

Comparative Example 45 (3S, 4R) -3-Amino-4-azido-2-oxoazetidine tosyl salt 63,79528

To a solution of 0.45 g of (3S, 4R) -4-azido-3-tritylamino-2-oxoazetidine in 4 ml of acetone is added 0.255 g of p-toluenesulfonic acid monohydrate under ice-cooling, and the mixture is stirred for 1 hour at room temperature. The solvent is removed by distillation, and the formed crystals are washed with ether. The crystals are collected by filtration to give 0.33 g of the tosyl salt of (3S, 4R) -3-amino-4-azido-2-oxoazetidine.

IR 0 cm -1; 3125, 2870, 2130, 1788, 1763, 1200, 1138, max 1125

Comparative Example 46 (35.45) -3-Amino-4-azido-2-oxoazetidine tosyl salt

To a solution of 1.3 g of (3S, 4S) -4-azido-3-tritylamino-2-oxoazetidine in 15 ml of acetone is added 0.736 g of p-toluenesulfonic acid monohydrate. The mixture is treated as described in Comparative Example 45 to give 0.886 g of the tosyl salt of (3S, 4S) -3-amino-4-azido-2-oxoazetidine.

KBr IR 1 cm -1; 3070, 2110, 1778, 1762, 1195, 1122, 1030, max 1010. Comparative Example 47 (35.45) -4-Azido-3- (D-2- (4-ethyl-2,3 dioxo-1-piperatsiinikarboksiamido) -2-tienyyliasetamido) -2-oxoazetidine

To a suspension of 0.565 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetic acid in 20 ml of methylene chloride are added, under ice-cooling, 0.189 g of trimethylchlorosilane and 0.176 g of triethylamine, which then the mixture is stirred for 30 minutes at room temperature and then cooled to -25 to -20 ° C. To this cooled mixture are added 0.127 g of DMF and 0.104 g of diphosgene, followed by stirring for 2 hours at the same temperature.

64 79528

On the other hand, 0.46 g of the tosyl salt of (3S, 4S) -3-amino-4-azido-2-oxoazetidine in 15 ml of methylene chloride, 0.243 g of pyridine and 2 ml of propylene oxide -25 ...- 20 are added to a suspension of ° C. To the mixture prepared above, the solution thus prepared is added, and the whole mixture is stirred during Turin at 0 ° C. The methylene chloride is removed by distillation, and the residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 0.546 g of (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2 , 3-dioxo-1-piperatsiinikarboksiamido) -2-tienyyliasetamido) -2-oksoat-setidiinia.

KBx IR 0 cm-1; 3270, 2100, 1781, 1670, 1500 max PMR (DMSO-d 6, ppm); 1.09 (t, J = 7Hz, CH 3), 3.39 (q, J = 7Hz), -CH 2 -), 3.46-3.68 (m, -CH 2 -), 3.84-4.40 (m, -CH 2 -), 4.59 (dd , J = 2.7Hz, C3-H), 5.08 (d, J = 2Hz, C4-H), 5.74 -CH- (d, J = 7Hz, 1), 6.94-7.54 (m, arom.H), 9.02 (s, NH), 9.24 (d, J = 7Hz, NH), 9.70 (d, J = 7Hz, NH)

Comparative Example 48 (3S, 4R) -4-Azido-3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine

To a suspension of 0.475 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetic acid in 15 ml of methylene chloride is added 0.173 g of tr-methylchlorosilane and 0.161 g of triethylamine under ice-cooling, and the mixture stirred for 30 minutes at room temperature, then cooled to -25 ° C. 0.116 g of DMF and 0.095 ml of diphosgene are added to the mixture, and the mixture is stirred for 2 hours at the same temperature, then cooled to -70 ° C. To the thus cooled mixture are added 0.222 g of pyridine, 0.33 g of the tosyl salt of (3S, 4S) -3-amino-4-azido-2-oxoazetidine and 2 ml of propylene oxide, respectively. The temperature of the mixture is raised to 0 ° C within one hour, while stirring the mixture 79528 65, followed by further stirring at 0 ° C for one hour. The methylene chloride is then removed by distillation and the residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 0.337 g of (3S, 4R) -4-azido-3- (2- (4-ethyl-2,3 -dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine.

KBr IR 0 cm-1; 3270, 2105, 1778, 1710, 1672, 1502 max PMR (DMSO-d 6, ppm); 1.09 (t, J = 7Hz, CH 3), 3.30-3.68 (m, -CH 2 -), 3.40 (q, J = 7 Hz, -CH 2 -), 3.77-4.05 (m, -CH 2 -), -CH- 5.02 -5.40 (m, C 3 -H, C 4 -H), 5.85 (d, J = 8Hz, *), 6.93 7.52 (m, arom.H), 9.03 (s, NH), 9.42 (d, J = 8Hz, NH), 9.80 (d, J = 8 Hz, NH).

Comparative Example 49 (3S, 4S) -4-Azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine

To a solution of 0.127 g of DMF in 5 ml of methylene chloride is added 0.104 ml of diphosgene at -10 ° C. The mixture is stirred for 30 minutes at room temperature, then 15 ml of a methylene chloride solution containing 0.483 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid and 0.176 g of triethylamine are added at -70 ° C. The mixture is stirred for 2 hours at -25 ° C, then cooled to -70 ° C and 0.352 g of triethylamine, 0.40 g of (3S, 4S) -3-amino-4-azido-2-oxoazetidine tosyl salt are added. and 2 ml of propylene oxide. The temperature of the mixture is raised to room temperature within one hour with stirring, followed by cooling on ice for one hour. The separated crystals are collected by filtration to give 0.383 g of (3S, 4S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine.

KB £ IR 0 cm -1; 3265, 2110, 1755, 1678, 1545 max and 66 79528 PMR (DMSO-d 6, ppm); 3.90 (s, CH 3), 4.35 (s, -CH 2 -), 4.70

S H

dd, J = 2.8Hz, C3-H), 5.13 (d, J = 2Hz, C4-H), 7.45 (s, Y).

9.13 (s, NH), 9.44 (d, J = 8 Hz, NH).

Comparative Example 50 (3S, 4R) -4-Azido-3- (2- (2-chloroacetamidodiazol-4-yl) -2-methoxyiminoacetamido-2-oxoazetidine

Applying the procedure of Comparative Example 49, but using 0.40 g of the tosyl salt of (3S, 4S) -3-amino-4-azido-2-oxoazetidine, 0.375 g of (3S, 4R) -4-azido-3- (2- (2-chloroacetamidodiazol-4-yl) -2-methoxyiminoacetamido-2-oxoacetidine δ gr: IR cm -1; 3260, 2110, 1768, 1670, 1540 max: PMR (DMSO-d 6, ppm); s, CH3), 4.35 (s, -CH2-), 5.18,

, H

5.40 (m, C3-H, C4-H), 7.34 (s, T). 9.07 (s, NH), 9.59 (d, J = 8Hz, NH).

Comparative Example 51 (3R, 4S) -4-methylthio-3-tritylamino-2-oxoazetidine (A) and (3R, 4R) -4-methylthio-3-tritylamino-2-oxoazetidine (B)

To a solution of 4.24 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-oxoazetidine in 30 ml of methanol is added, under ice-cooling, 8.64 ml of a 15% aqueous solution of sodium methyl sulfide. The mixture is stirred for one hour at room temperature. The solvent is removed by distillation, and the residue is dissolved in ethyl acetate and washed with water. The ethyl acetate is removed by distillation and the residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 1.43 g of (3R, 4S) -4-methylthio-3-tritylamino-2-oxoazetidine (A) and 1.62 g of (3R, 4R) -4-methylthio-3-tritylamino-2-oxoazetidine (B).

(A) 67 79528 KBr IR ν cm -1; 3275, 1750 max PMR (CDCl 3, ppm); 1.65 (s, CH 3), 3.00 (broad s, NH), 4.03-4.20 (m, C 3 -H, C 4 -H), 7.01 (s / NH) / 6.80-7.90 (m, arom.H) (B) KBr IR i) cm -1; 3260, 1752 max PMR (CDCl 3, ppm); 1.73 (s, CH 3), 2.98 (d, J = 8Hz, NH), 4.15 (d, J = 5Hz, C 4 -H), 4.26 (dd, J = 5.8Hz, C 3 -H), 6.83 (s, NH), 7.00-7.80 (m, aroma H)

Comparative Example 52 (3R, 4S) -3-Amino-4-methylthio-2-oxoazetidine tosyl salt

To a solution of 0.9 g of (3R, 4S) -4-methylthio-3-tritylamino-2-oxoazetidine in 5 ml of acetone is added 0.503 g of p-toluenesulfonic acid monohydrate. The mixture is treated as described in Comparative Example 45 to give 0.69 g of the tosyl salt of (3R, 4S) -3-amino-4-methylthio-2-oxoazetidine.

KBX *

IrO cm -1; 3100-2900, 1798, 1770, 1755, 1190, 1165, 1120 max. Γ '. *. Comparative Example 53 (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxy-iminoacetamido) -4-methylthio-2-oxoazetidine

To a solution of 0.228 g of DMF in 5 ml of methylene chloride is added 0.137 ml of diphosgene at -10 ° C. The mixture is then stirred for 30 minutes at room temperature, cooled to -70 [deg.] C. and 15 ml of a methylene chloride solution containing 0.80 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid and 0.316 g are added. g of triethylamine. The mixture is stirred for 2 hours at -25 ° C, then cooled to -70 ° C and 0.632 g of triethylamine, 0.69 g of (3R, 4S) -3-amino-4-methylthio-2-oxoazetidine tosyl ee 79528 salt and 2 ml of propylene oxide. The temperature of the mixture is raised to 0 ° C within one hour while stirring. The mixture is stirred for a further two hours at the same temperature, then concentrated and THF is added and the insoluble components formed are removed by filtration. The filtrate is concentrated and the residue is purified on a silica gel column (3: 3: 1 mixture of AcOEt, CHCl 3 and CH 3 OH as eluent) to give 0.461 g of (3R, 4S) -3- (2- (2-chloroacetamide). (thiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine.

KBr IR ^ cm-1; 3255, 1758, 1670, 1540, 1270, 1040 max PMR (DMSO-d 6, ppm); 2.14 (s, CH3) <3.90 (s, OCH3), 4.35 (s,

B

-CH 2 -), 4.57-4.90 (m, C 3 -H, C 4 -H), 7.40 (s, Y), 8.80 (s, NH), 9.37 (d, J = 9 Hz, NH), 12.88 (broad s, NH)! Comparative Example 54 (3R, 4S) -3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine

To a suspension of 0.552 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetic acid in 15 ml of methylene chloride is added, under ice-cooling, 0.20 g of trimethylsilyl chloride and 0.187 g of triethylamine. The mixture is stirred for 30 minutes at room temperature, then cooled to -25 ° C and 0.135 g of DMF and 0.11 ml of diphosgene are added and stirred for 2 hours at the same temperature. The mixture is then cooled to -70 ° C and 0.258 g of pyridine, 0.426 g of (3R, 4S) -3-amino-4-methyl-thio-2-oxoazetidine tosyl salt and 2 ml of propylene oxide are added thereto, respectively. The temperature of the mixture is raised to 0 ° C over 30 minutes with stirring, followed by stirring for a further hour. The reaction mixture is concentrated under reduced pressure. The residue is purified on a silica gel column to give 0.308 g of (3R, 4S) -3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine.

69,79528 KBr IR 2 cm -1; 3270, 1768, 1710, 1670, 1502, 1182 max

Comparative Example 55 (3R, 4R) -4-phenylthio-3-tritylaminooxoazetidine (A) and (3R, 4S) -4-phenylthio-3-tritylaminooxoazetidine (B)

To a solution of 5.0 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-oxoazetidine in 100 ml of methanol are added 1.6 ml of thiophenol and 15.5 ml of 1N aqueous sodium hydroxide solution under ice-cooling. . The mixture is stirred for 20 minutes at the same temperature and for a further 50 minutes at room temperature. The separated crystals are collected by filtration to give 2.35 g of (3R, 4R) -4-phenylthio-3-tritylaminooxoazetidine (A). The filtrate is concentrated, and the residue is dissolved in ethyl acetate, washed with water and concentrated. The residue is purified on a silica gel column (eluent: ethyl acetate and n-h, 1: 1 mixture of exane) to give 2.65 g of (3R, 4S) -4-phenylthio-3-tritylaminooxoazetidine (B).

{A) KBr IR ύ cm-1; 3290, 1755, 1725 max PMR (CDCl 3, ppm); 3. 10 (d, J = 8Hz, NH), 4.48-4.83 (m, C3-H, C4-H), 6.08 (s, NH), 7.17-7.65 (m, aroma H) (B) KBr IR ^ cm- 1; 3300-3220, 1755 max PMR (CDCl 3, ppm); 2.87 (d, J = 8Hz, NH), 4.00 (dd, J = 2.9Hz, C3-H), 4.37 (d, J = 2Hz, C4-H), 6.52 (s, NH), 7.10-7.70 ( m, aroma H) • Comparative Example 56 (3R, 4R) -3-Amino-4-phenylthio-2-oxoazetidine tosyl salt

To a solution of 1.5 g of (3R, 4R) -4-phenylthio-3-tritylamino-2-oxoazetidine in 20 ml of acetone is added 0.72 g of p-toluenesulfonic acid monohydrate under ice-cooling.

70 79528

Applying the procedure of Comparative Example 45, the tosyl salt of 1,25 (3R, 4R) -3-amino-4-phenylthio-2-oxoazetidine is obtained.

KB r * IR>) cm-1; 3090, 2850, 2740, 1780, 1205, 1,175, 1118 max

Comparative Example 57 (3R, 4S) -3-Amino-4-phenylthio-2-oxoazetidine tosyl salt

To a solution of 2.65 g of (3R, 4S) -4-phenylthio-3-tritylamino-2-oxoazetidine in 20 ml of acetone is added, under ice-cooling, 1.26 g of p-toluenesulfonic acid monohydrate, followed by applying Example 45. 1.9 g of the tosyl salt of (3R, 4S) -3-amino-4-phenylthio-2-oxoazetidine are obtained.

KBr IR>) cm -1; 3240, 3140, 3050, 2980, 2920, 1807, 1210, 1200, max 1168, 1128

Comparative Example 58 (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine

Applying the procedure of Comparative Example 49, but using 0.19 g of DMF, 0.156 ml of diphosgene, 0.732 g of (3R, 4S) -3-amino-4-phenylthio-2-oxoazetidine tosyl salt and 2 ml of propylene oxide, 0.649 g of 3R , 4S) -3- (2- (2-klooriasetamidotiatsol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine.

KBr IR 0 cm-1; 3240, 3170, 3055, 1752, 1652, 1535 max PMR (DMSO-d 6, ppm); 3.90 (s, CH 3), 4.37 (s, -CH 2 -), 4.69

S H

(dd, J = 2.8Hz, C3-H), 4.98 (d, J = 2Hz, C4-H), 7.34 (s, y '), 7.30-7.60 (m, aroma H), 9.04 (s, NH ), 9.38 (d, J = 8Hz, NH), 12.84 (s, NH) and 7 79528

Comparative Example 59 (3R, 4S) -3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-phenylthio-2-oxoazetidine

Applying the method of Comparative Example 54 but using 0.57 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid; 0.212 g of trimethylchlorosilane; 0.143 g DMF; 0.193 g diphosgene; 0.273 g of pyridine; 0.55 g of the tosyl salt of (3R, 4S) -3-amino-4-phenylthio-2-oxoazetidine and 2 ml of propylene oxide give 0.696 g of (3R, 4S) -3- (2- (4-ethyl-2, 3-dioxo-1-piperazine-carboxamido) -2-phenylacetamido) -4-phenylthio-2-oksoatse polypeptide.

KBr IR) cm -1; 3270, 1772, 1710, 1670, 1502 max

Comparative Example 60 (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -4-methylthio-2-oxoazetidine

To a solution of 0.976 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetic acid and 0.304 g of triethylamine in 20 ml of methylene chloride are added, under ice-cooling, 0.625 g of powdered phosphorus pentachloride, and the mixture is stirred. at the same temperature for one hour. The reaction mixture is concentrated under reduced pressure, the residue is washed with n-hexane to which THF is added, after which the insoluble components are removed by filtration. The filtrate is added under ice-cooling to a solution of 0.913 g of (3R, 4R) -3-amino-4-methylthio-2-oxoazetidine p-toluenesulfonate and 0.910 g of triethylamine in 15 ml of THF. The mixture is stirred at room temperature for one hour, after which the mixture is filtered. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (eluent 1: 1 ethyl acetate / n-hexane) to give 0.960 g of (3R, 4R) -3- (D-2- (4-ethyl). -2,3-dioxo-1-piperazinicarboxamido) -2-thienylacetamido) -4-methylthio-2-oxoazetidine.

KBr IR λ) cm -1: 1760, 1710, 1673, 1500, 1130 max PMR (DMSO-d 6, ppm); 1. 10 (t, J = 4Hz, CH 3), 1.73 (s, CH 3), 3.53 (m , -CH 2 -), 4.00 (m, -CH 2 -), 4.83 (d, J = 4Hz, C 4 -H), 5.30 -CH- (dd, J = 4.6Hz, C 3 -H), 5.93 (d, J = 4Hz, ·), 6.90-7.63 (m, arom.

H), 8.90 (s, NH), 9.36 (d, J = 6Hz, NH), 9.83 (d, J = 4Hz, NH)

Comparative Example 61 (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine

To a solution of 0.833 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid and 0.304 g of triethylamine in 20 ml of methylene chloride is added 0.625 g of ground phosphorus pentachloride under ice-cooling, and the mixture is stirred for one hour. . The reaction mixture is concentrated under reduced pressure, the residue is washed with n-hexane and then THF is added. The insoluble components formed are removed by filtration, and the filtrate is added under ice-cooling to a solution of 0.913 g of (3R, 4R) -3-amino-4-methylthio-2-oxoazetidine p-toluenesulfonate and 0.910 g of triethylamine in 15 ml of THF: a. The mixture is stirred for one hour at room temperature, then filtered. The filtrate is concentrated under reduced pressure. The residue was washed with aqueous sodium bicarbonate and water, respectively, and dried to give 0.780 g of (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2 -oksoatsetidiinia.

KBr IR d cm-1: 1760, 1660, 1545, 1050 max PMR (DMSO-d 6 / ppnt); 2.06 (s, SCH3), 3.90 (s, OCH3), 4.36 (s, -CH2-), 4.93 (d, J = 4Hz, C4-H), 5.04 (dd, J = 4.6Hz, C3-H) , 7.50 (s, V), 8.84 (broad s, NH), 9.53 (d, J = 6Hz, NH), 12.90 (broad s, NH) 73,79528

Comparative Example 62 "- - (3R, 4R) -3- (3- (2,6-dichlorophenyl) -5-methyl-4-isooxazolylcarboxamido) -4-methylthio-2-oxoacetidine

To a solution of 0.608 g of (3R, 4R) -3-amino-4-methylthio-2-oxoazetidine p-toluenesulfonate and 0.380 g of pyridine in 10 ml of methylene chloride is added, under ice-cooling and stirring, a solution of 0.581 g of 3 - (2,6-dichlorophenyl) -5-methyl-4-isooxazolylcarbonyl chloride in 5 ml of methylene chloride. The reaction mixture is stirred for 1 hour at room temperature, then concentrated under reduced pressure. . and the residue is purified by chromatography on a column of silica gel (eluent 1: 1 mixture of ethyl acetate and n-hexane) to give 0.550 g of (3R, 4R) -3- (3-: (2,6-dichlorophenyl) -5- methyl-4-isooxazolylcarboxamido) -4-methylthio-2-oxoazetidine.

*** * KBr IR 1 cm -1; 1760, 1660, 1595, 1500 max PMR (CDCl 3, ppm); 1.90 (s, CH 3), 2.83 (s, CH 3), 4.70 (d, J = 4 Hz, C 4 - H), 5.50 (dd, J = 4.8Hz, C5-H), 6.13 (d, J = 8Hz, NH), 6.50 (broad s, NH), 7.40 (s, aroma H)

Comparative Example 63 (3R) -4-Fluoro-3-tritylamino-2-oxoazetidine

To a solution of 0.400 g of (3R, 4R) -4-methylsulfonyl-3-tritylamino-2-oxoazetidine in 2 ml of DMF is added 0.590 g of tetra-n-butylammonium fluoride, and the mixture is stirred for 30 minutes at room temperature. Ice water and ethyl acetate are added to the reaction mixture. The ethyl acetate layer is separated and washed with water, then concentrated. The residue is purified on a silica gel column (1: 1 mixture of ethyl acetate and n-hexane as eluent) to give 0.282 g of (3R) -4-fluoro-3-tritylamino-2-oxoazetidine.

74 79528 KB x * IR 0 cm -1; 1765, 1480, 1440, 1300, 750, 695 max

Comparative Example 64 p-Toluene sulfonate of (3R) -3-amino-4-fluoro-2-oxoazetidine

To a solution of 3.3 g of (3S) -4-fluoro-3-tritylamino-2-oxoazetidine in 10 ml of acetone is added 1.82 g of p-toluenesulfonic acid monohydrate, and the mixture is treated as described in Comparative Example 45 to give 2.67 g of (3R) -3-amino-4-fluoro-2-oxoazetidine p-toluenesulfonate are obtained.

KBr IRO cm -1; 1790, 1170, 1035, 1010 max; i

Comparative Example 65

Isomer A and (3R, 4S) -isomer B of (3R, 4R) -4- (1-methyl-1H-tetrazol-4-yl) -thio-3-tritylamino-2-oxoazetidine

Applying the method of Comparative Example 36, but using a mixture prepared by adding a solution of 0.965 g of the sodium salt of 5-mercapto-1-methyltetrazole in 10 ml of methanol to a solution of 2.7 g of (3S, 4S) -4 -acetoxy-4-tritylamino-2-oxoazetidine in 30 ml of methanol gives 0.70 g of (3R, 4R) -4- (1-methyl-1H-tetrazol-4-yl) -thio-3-tritylamino-2 -oxoazetidine isomer (A) and 1.32 g of (3R, 4S) -isomer (B).

(A) 1 KBx1 IR 0 cm -1; 3300, 1779, 1728 (olake), 1442, 1340, 1331, max 700 75 79528 PMR (ClX: i3, ppm); 3.75 (e, CH3), 4.93 (q. J-4.12Hz, C3-H), 5.85 (d, J <8H2, C4-H), 6.59 (broad s, NH), 7.0-7.6 (m, arom H) (B) 3320, 1774, 1441, 1367, 1225, 1030, 698 δ PMR (CDCl 3, ppm), 3.72 (e, CH 3), 5.04 (broad sC-jH), 5.37 (d, J »2Hz, C 4 -H), 6.72 (broad β, ΝΗ) , 7.0-7.6 (m, aroma H)

Comparative Example 66 (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-4-yl) thio-2- oxoacetidine. . To a solution of 0.535 g of (3R, 4R) -4- (1-methyl-1H-tetrazol-4-yl) -thio-3-tritylamino-2-oxoazetidine in 5 ml of acetone is added 0.230 g of p- toluenesulfonic acid monohydrate, and the mixture is stirred for 3 hours at room temperature. The reaction mixture is concentrated and the residue is washed with ether and then dissolved in 15 ml of THF.

On the other hand, 0.336 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid is treated as described in Comparative Example 61 to give a solution of the corresponding acid chloride in 10 ml of THF. The solution thus prepared is added under ice-cooling to a solution prepared by adding 0.270 g of triethylamine to the above solution in 15 ml of THF. Ethyl acetate is added to the reaction mixture, followed by washing with water and removing the solvent by distillation. The residue is purified on a silica gel column (eluent: AcoEt, CHCl 3 and CH 3 OH 3: 3: 1) to give 0.380 g of (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxy-iminoacetamido) -4- (1-methyl-lH-tet ratsol-4-yl) thio-2-oxoazetidine.

76 79528 IR vKBrc® ”1; 3220, 1790, 1679, 1540, 1365, 1332, 1045 max PMR (DMSO-d 6, ppm); 3.72 (s, CH3), 3.37 (s, CH3), 4.35 (s, -CH2-), 5.73 (dd, J »4.8Hz, C3-H), 6.38 (d, J = 4Hz # C4-H), 7.23 (8, ^), 9.20 (broad s, NH), 9.50 (d, J «8Hz, NH), 12.84 (broad s, NH)

Comparative Example 67 (3R / 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-4-yl) thio-2- oxoazetidine

Applying the procedure of Comparative Example 66, a solution of 1.12 g of (3S, 4S) -4- (1-methyl-1H-tetrazol-4-yl) -thio-3-tritylamino-2-oxoazetidine in 5 ml is treated: acetone, 0.491 g of p-toluenesulfonic acid monohydrate and 0.788 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid to give 0.650 g of (3R, 4S) -3- (2 - (2-klooriasetamidotiatsol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-4-yl) thio-2-oxoazetidine.

»VSfor1! 3250, 1787, 1870, 1540, 1385, 1038, 820 FMK (DHSO-d6, ppm) | 3.88 (a, CB3), 3.92 (s, CH3), 4.36 (·, -CH2-), 5.38 (dd, J-2.8H *, C3-H), 6.22 (d, J-2Hx, C4-H) ), 7.43 (·, ^), 9.40 (a, HB), 9.51 (d, J-ΒΗζ, ΜΗ), 12.84 (broad s, HH)

Comparative Example 68 (3S, 4S) -4-Azido-3- (2- (2-tritylaminothiazol-4-yl) -carboxymethyliminooxy) -2-methylpropionamido) -2-azetidinone

To a suspension of 1.13 g of 2- (1-carboxy-isopropoxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid in 15 ml of methylene chloride is added 0.454 g of dicyclohexylcarbodiimide (of which DCC is used) and the mixture 77 79528 is stirred at room temperature for 20 minutes, after which the insoluble components are removed by filtration.

On the other hand, 0.598 g of (3S, 4S) -3-amino-4-azido-2-azetidinone p-toluenesulfonate are suspended in 10 ml of ethylene chloride, and 0.159 g of pyridine and then 10 ml of DMF are cooled under ice-cooling. To the resulting solution is added the filtrate prepared above, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated and the residue is purified by column chromatography on silica gel (eluent: AcoEt, CHCl 3 and CH 3 OH 3: 3: 1) to give 0.63 g of (3S, 4S) -4-azido-3- (2- ( 2-tritylaminothiazol-4-yl-phenyl) acyliminoxy carboxymethyl) -2-metyylipropioniamido) -2. . azetidinone.

Ilt vjjjjcwTlt 3400-3200, 2105, 1760, 1600, 1520 PMR (DMSO-d 6, ppm): 1.36 (s, CH 3), 1.41 (>, CB 3), 4.49 (dd, J-2.8 Hz, C 3 -H) , 4.96 (d, J «2Hz, C4-H), 6.73 (s, YH), 7.14 ^ 7.55 (*, aro · H), 8.94 (·, ΝΗ), 9.88 (d, J = 8Hs, VB)

Comparative Example 69 (3R, 4R) -3- (2- (1- (2-Trimethylsilylethoxycarbonyl) -1'-isopropoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido) -4-methylthio-2 -atsetidinoni

A mixture of 0.615 g of 2- (1- (2-trimethylsilylethoxycarbonyl) -isopropoxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid, 0.180 g of N-hydroxy-5-norbornene-2, 3-Dicarboximide and 0.210 g of DCC in 6 ml of methylene chloride are stirred at room temperature. The precipitates are removed by filtration. 0.305 g of (3R, 4R) -3-amino-4-methylthio-2-azetidinone p-toluenesulfonate and then a solution of 0.105 g of triethylamine in 10 ml of methylene chloride are added to the filtrate, and the mixture is stirred for 4 hours. The reaction mixture is concentrated and the residue is purified by column chromatography on silica gel (eluent: AcOEt, CHCl 3 and n-hexane 2: 2: 1 78 79528) to give 0.40 g of (3R, 4R) -3- (2- ( 1- (2-trimethyl-silylethoxycarbonyl) isopropoxy-imino) -2- (2-trityl-aminothiazole-4-yl) acetamido) -4-methylthio-2-azetidinone.

IR vJ? * »" 1: 1760, 1670, 1520

nix

PMR (DMSO-d 6, ppm): 0.03 (e, CH 3), 0.9 (t, J «8Hz, -CH 2 -), 1.5 (», CH 3), 2.10 (b, CH 3), 4.90 (d, J «4Hz , C4-H), 5.40 (dd, J-4.8H *, C3-H), 7.0-7.6 (m, aroma H)

Comparative Example 70

Isomer A of (3R, 4R) -4-methoxycarbonylmethylthio-3-tritylamino-2-oxoazetidine and the corresponding (3R, 4S) -isomer B

1) To a solution of 1.93 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-oxoazetidine in 100 ml of methanol is added a solution of 0.64 g of sodium thioglycolate sodium salt, followed by ice-cooling. and mixed. After 1 hour: the solvent is removed by distillation and the residue is dissolved in ethyl acetate. The solution is washed with water, then the solvent is removed by distillation and the residue is purified by column chromatography on silica gel (eluent: 11: 1 mixture of ethylene chloride and ethyl acetate) to give 1.38 g of (3R, 4R) -4-methoxycarbonylmethylthio-3-tritylamino -azetidine isomer (A) and 0.92 g of the corresponding (3R, 4S) -isomer (B).

VDr Ί (A) IR ν cm -1: 3310, 1760, 1730, 1487, 1445, 1240, 1152, 700 PMR (DMSO-d 6, ppm): 2.86, 3.08 (ABq, J «15Hz, -CH 2«) , 3.61 (s, CH3), 2.98 (d, J «9Hz, NH), 4.42 (dd, J« 6.9Hz, C3 - H) 4.43 (d, J «6Hz, C4-H), 6.67 (s, NH), 6.8 ^ 7.5 (m.arom H) (B) IR vJSfcnf1 * 1760, 1730, 1275, 1150, 697

IDAX

PMR (OMSO-d 6, ppm): 2.93 (broad s, -CH 2 -), 3.57 (s, CH 3), 3.9% 4.2 (m, C 3 -H, C 4 -H), 6.55 (broad s, NH), 6.8 7.5 (m, arom H) 79 79528 2) Dissolve 0.59 g of the (3R, 4R) -trityl derivative obtained in 1) in 3 ml of acetone, add 0.251 g of p-toluenesulfonic acid monohydrate, followed by stirring for 1 hour. time at room temperature. The solvent is removed by distillation to give (3R, 4R) -3-amino-4-methoxycarbonylmethyl-thio-2-oxoazetidine.

The compound thus obtained is dissolved in a mixture of 20 ml of water and 15 ml of tetrahydrofuran, and 0.388 g of sodium bicarbonate is added under ice-cooling and stirring. The pH of the reaction mixture is maintained at 7-8 by the addition of sodium bicarbonate, and 0.571 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride is added to the reaction mixture.

The reaction mixture is stirred for 30 minutes at room temperature, after which time it is extracted with ethyl acetate. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: chloroform: methanol = 4: 4: 1) to give 0.50 g of (3R, 4R) -3- (2- (chloroacetamidothiazol-4-yl) - 2-methoxy-iminoasetami-do) -4-metoksikarbonyylimetyylitio-2-oxoazetidine.

IR 3252, 1762, 1745, 1663, 1540, 1160, 1052. . max PMR (DMSO-d 6, ppm) t 3.46 (s, -CH 2 -), 3.68 (s, CH 3), 3.89 (s, CH 3), 4.37 (s, C 1 CH 2 -), 5.09 (d, J = 4Hz, C 4 > H), 5.40 (dd, J »4.8Hz, C3-H), 7.48 (8, ^), 8.80 (broad β, ΝΗ), 9.50 (d, J * 8Hz, NH), 12.86 (broad β, ΝΗ)

Comparative Example 71 (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-oxoacetidine is prepared by applying the method of Comparative Example 70.

80 79528 KB jc IR cm -1; 3252, 1763, 1735, 1660, 1540, 1278, 1160 max PMR (DMSO-d 6, pprn) i 3.5 «(*, - CH 2 -), 3.68 (e, CH 3), 3.91 (s, CH3), 4.36 (*, C1CH2-), 4.75 <dd, J-2.8Hz, C3-H), 4.82 (d, J »2Hx, C4-H), 7.41 (β, γΗ), β .βΙ (β, ΝΗ), 9.36 (d, J-8H *, NH), 12.38 (broad., NH)

Comparative Example 72 1) (3R, 4R) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-n-butylthio-2-oxoazetidine is prepared by applying the method of Comparative Example 70.

IR '' JJfc · -1 · 3255, 1758, 1660, 1540 ΧαΧ PMR (DMSO-d 6, ppni): 0.88 (m, CH 3), 1.46 (m, -CH 2), 2.56 (t, J «7Hz, - CH2-), 3.89 (s, CH3), 4.34 (s, -CH2-), 4.98 (d, J »5Hz, C4-H), 5.38 (dd, J * 5.9Hz, C3» H), 7.49 ( ·, ΓΗ), 8.81 (β, ΝΗ), 9.47 (d, J-9Hz, NH) 2) By applying the method of Comparative Example 70, the corresponding (3R, 4S) -isomer is prepared.

KBr .1 IR νmaxcra 1 3265 '1762 »1660, 1540 PMR (DMSO" dg, ppm): 0.89 (t, J «7Hz, CH3), 1.48 (ro, -CH2 -), 2.65 (t, J-7Hz, -CH 2 -J, 3.91 (e, CH 3), 4.37 (a, -CH 2 -), 4.68 (dd, J-2.9Hz, C 3 -H), 4.68 (d, J 2 Hz, C 4 -H), 7.40 (β, γΗ), 1.81 (β, ΝΗ), 9.34 (d, J-9Hx, NH)

Comparative Example 73 1) (3R, 4R) -3- 2- (2-chloroacetamidothiazol-4-yl) -2- (not 79528 methoxyiminoacetamido) -4-isopropylthio-2-oxoacetidine is prepared by applying the method of Comparative Example 70.

IR νϊ ^ ση »" 1 »3250, 1750, 1660, 1540, 1050

MX

PMR (DNAO-dg, ρρη) 1.20, 1.25 (min. D, J «6Hz, CH3), 3.06 (m," ^ H ·), 3.I8 (*, CH3), 4.35 (s, C1CH2-), 5.06 (d, J-5Ht, C3-H), 5.41 (dd, J-5.9Hz, C4-H), 7.46 (β, γΗ), 8.74 (broad β, ΝΗ), 9.36 (d, J «9Hz , ΝΗ), 12.86 broad s, MH) 2) The corresponding (3R, 4S) -isomer is prepared by applying Comparative Example 70.

Kftr - 1 IR νmaxcm * 3275 '1760' 1689 '166 ° »158 ° * 1542' 1365, 1322, 1045 PMR (DMSO-d6, ppm) i 1.28 (d, J« 7Hz, CH3), 3.15 (m, ' (H,), 3.90 (e, CH3), 4.37 (e, ClCH2-), 4.68 (dd, J = 2.8Hz, C3-H), 4.74 (d, J-2Hz, C4-H), 7.39 ( ·, ΓΗ), 8.83 (e, NH), 9.35 (d, J-8Hz, NH), 12.88 (broad s, NH)

Comparative Example 74 (3R, 4S) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4 - (((n-propylthio) thiocarbonyl) thio) -2-oxoazetidine is prepared by applying the method of Comparative Example 70.

IR viSc · '11 3250' 177 ° »1540, 1263, 1043 PMR <DMSO-d 6, ppm): 1.97 (t, J-7Hz, CH 3>, 1.70 (m, -CH 2>), 3.39 (t, J 7Hz, -CH2-), 3.90 (e, CH3), 4.36 (s, C1CH2-), 5.05 (dd, J-2.8Hz, C3-H), 5.73 <d, J (2H *, C4-H) , 7.40 (·, γΗ), 12.8 (broad S, MH) 82 79528

Comparative Example 75 1) (3R, 4R) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio-2-oxoacetidine is prepared by applying the method of Comparative Example 70.

IR vKBrcnfl; 1765, 1665, 1545, 1050 max PMR (DMSO-df, ppA) i 1.0 ^ 2.0 (m, -CH2-), 3.90 (b, CH3), 4.36 (», C1CH2«), 5.10 (d, J-4Hz) , C4-H), 5.40 (dd, J-4.8Hz, C3-H), 7.48 (δ, γΗ), 8.76 (broad s, NH), 9.42 (d, J-8H *, NH) 2) Similar The (3R, 4S) -isomer is prepared by applying the method of Comparative Example 70.

IR 1760, 1660, 1540, 1040 PMR (DMSO-d 6, ppm) I 1.0 ^ 2.1 (m, -CH 2 -), 3.90 (s, CH 3) 4.36 (s, C 1 CH 2 -), 4.66 (dd, J «2, 8Hz, C3-H), 4.74 (d, J <2H *, C4-H), 7.38 (s, yH), 8.80 (s, NH) 9.36 (d, J »8H *, HH)

Comparative Example 76 3-Benzyloxycarboxamido-4-ethoxy-3-methoxy-2-oxoazetidine is prepared by applying the method of Comparative Example 1.

IR 3275, 1780, 1690, 1495, 1120 max PMR (DMSO-d 6, ppm) I 1.15 (t, J-7Hs, CH 3), 3.48 (s, CH-j), 3.62 (q, J «7iU, -CH 2 -), 4.91 (s, C4 (H), 5.14 (s, -CH2-), 5.88 (s, NH), 7.30 (s, MH), 7.30 (s, arom H) 83 79528

Comparative Example 77 (3R) -4 - ((2-acetamidoethyl) thio) -3- (2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine

To a solution of 1.4 g of (3S, 4S) -4-acetoxy-3-tritylamino-2-oxoazetidine in 30 ml of methanol is added, with stirring and ice-cooling, a solution of 0.51 g of the sodium salt of N-acetylcysteamine. In 30 ml of methanol. After 30 minutes, the solvent is removed by distillation and the residue is dissolved in ethyl acetate.

The solution is washed with water and then the solvent is removed to give 1.6 g of 4- (2-acetamidoethyl) thio-3-tritylamino-2-oxoazetidine, which is dissolved in 10 ml of acetone.

To this solution is added 0.682 g of p-toluenesulfonic acid monohydrate, followed by stirring for 45 minutes.

The acetone is removed by distillation, and the residue is collected by filtration and washed with ether to give 3-amino-4- (2-acetamidoethyl) thio-2-oxoazetidine p-toluenesulfonate. This is dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran, and 0.904 g of sodium bicarbonate is added to the solution. The pH of the reaction mixture is maintained in the range of 7-8, and sodium bicarbonate and 1.432 g of 2- (2-acetamidothiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride are added.

The reaction mixture is stirred for 30 minutes, then extracted with ethyl acetate and washed with water. The extract is distilled to remove the solvent. Ether is added to the residue and the solid product formed is collected by filtration to give 1.5 g of (3R) -4 - ((2-acetamidoethyl) thio) -3- (2- (2-chloroacetamido-thiazol-4-yl) - 2-methoxyiminoacetamido) -2-oxoacetidine.

i 84 79528 VBf.1 IR vmaxca '3370' 3270, 1735, 1650, 1530, 1360, 1270, 1040 PMR (DMSO-d6, ppm) * 1.82, 1.84 (a, CH3), 2.68 (m, -CH-, -), 3.89, 3.91 (y. B, CH3>, 4.40 (s, C1CH2-), 4.74 (d, J * 2Hz, C4-H), 5.02 (d, J * 5Hz, C4-H), 4.67 ( dd, J-2.8H *, C3-H), 5.37 (dd, J-5.8Hz, C3-H) 7.40, 7.48

Comparative Example 78 (3S ', 4R) -4-Azido-3- (D-2-thienyl-2-ureidoacetamido) -2-oxo-azetidine

To a suspension of 0.8 g of D-2-thienyl-2-ureidoacetic acid in 12 ml of acetonitrile is added 0.952 g of thionyl chloride under ice-cooling, and the mixture is stirred for 10 minutes, then evaporated to dryness to give crystals which are collected by filtration. On the other hand, to a suspension of 0.598 g of (3S, 4R) -3-amino-4-azido-2-oxoazetidine p-toluenesulfonate in 20 ml of methylene chloride, 0.64 g of pyridine are added to -70 ° C, 2 ml of propylene oxide, the crystals prepared above and 10 ml of dimethylformamide, respectively. The reaction mixture is stirred for 3 hours at 0 ° C, then concentrated. The product obtained is purified by chromatography on a silica gel column (2: 1 mixture of ethyl acetate and hexane as eluent) to give 0.55 g of (3S, 4R) -4-azido-3- (D-2-thienyl-2-ureidoacetamido) -2- oxo-azetidine.

VDr IR 'max01'1 * 3260' 211'1770 * <50, 1535 PMR (DMSO-d6, ppm): 5.10-5.40 (in, C3-H, C4-H), 5.69 (d, J-8H *, "fH '), 5.73 (e, NH 2), 6.76 (d, J-βΗζ, ΝΗ), 6.90-7.60 (m, Aron H), 8.99 (s, NH), 9.25 (d, J-8Hz, NH) 85 79528

Comparative Example 79

In the same manner as in Comparative Example 54, (3R, 4S) -3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -4-phenylthio-2-oxoazetidine is prepared.

IR 3255 '1775' 1695 '1665 »1505' 1480 * 1268 PMR (DMSO-d 6, ppm) t 3.19ί> 3.43 (m, -CH 2 -), 3.62x3.84 (m, -CH 2 -), 4.56 (dd , J-2.9Hz, C3-H), 4.83 (d, J «2Hz, C4-H), 5.39 (d, J» 8Hz, ~ 1H '), 7.33 (t, Aron, 8), 7 * 36 (a, Aron, H), 7.5S (a, NH), 8.95 (a, NH), 9.03 (d, J-8H *, NH), 9.19 (d, J «9Hz, NH) .... t

Comparative Example 80

Applying the procedure of Comparative Example 54, (3S / 4S) -4-azido-3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -2-oxoazetidine is prepared.

KBr-1 IR νmaxcra: 3300% 3240, 2090, 1772, 1705, 1660, 1505, 1255 PMR (DMSO-d 6, ppm): 3.10x3.40 (in, -CH 2 -), 3.60x3.88 (m, - CH2-), 4.64 (dd, J = 2.8Hz, C3-H), 5.02 (d, J * 2Hz, C4-H), 5.42 (d, J-8HZ, ~ ^ H "), 7.36 (a, aroma, H), 7.54 (s, NH), 8.98 (a, NH), 9.00x9.20 (m, NH)

Comparative Example 81 (3S-trans) -3-Methoxy-4-methylthio-3-p-nitrobenzyloxy-carboxamido-2-oxoazetidine ee 79528 0.405 g of methyl (3S-trans) -3-methoxy-4-methylthio- 3-p-Nitrobenzyloxycarboxamido-2-oxoazetidine-1- (cC-isopropylidene) acetate with 0.283 g of potassium permanganate in a solution of 7.5 ml of pyridine and 0.5 ml of water to give 0.096 g of (3S-trans) - 3-Methoxy-4-methyllithio-3-p-nitrobenzyloxy-carboxamido-2-oxoazetidine.

PMR <CDCl 3, ppw) i 2.10 (», CH 3), 3.51 (», CH 3), 4.72 <e, C 4 -H), S.29 (», - CH 2 -), 6.22 (e, NH), 6.98 ( ·, ΝΗ), 7.55, 8.17 (min. D, J «9Hz, arom, H)

Comparative Example 82

Applying the procedure of Comparative Example 16, (3S-trans) -3- (D-2- (4-cyclohexyl-2,3-dioxo-1-piperazine carboxamido-2-phenylacetamido) -3-methoxy-4-methylthio-2- oxoazetidine.

IR Vcmaxcm'1: 3270 '292S »1770' 1705 '1670' 1500 '1170 PMR (CDCl3, ppm): 1.94 (e, CH3), 3.39 (s, CH3),

4.68 (e, C4-H), 5.57 (d, J * 7Hz, “^ H”) # 3.3 ^ 4.1 (m, -CH2 ~), 6.95 (s, NH), 7.2 ^ 7.6 (m, ar ), 7.50 (s, NH

9.84 (d, J-7Hz, NH)

Comparative Example 83

Applying the procedure of Comparative Example 54, (3S, 4S) -4-azido-3- (D-2- (3-methyl-3- (methylcarbamoyl) -1-ureido) -2-phenylacetamido) -2-oxoacetidine is prepared.

4 87 7 9 5 2 8 IR vifici.-1. 327 $ 2X0, 1770, 1675, 1495

IQAX

PMR (DMSO-d 6, ppcn): 2.67 (d, J <4 Hz (CH 3), 3.08 (e, CH 3), 4.55 (m, C 3 -H), 5.00, 5-.02 (min. D, J-2 Hz) , C4-H), 5.37 (d, J "7H *," ^ H "*), 7.36 (e, aroma, H), 8.98 (e, NH), 9.07 (d, J-1H *, MH), 9.87, 9.92 (min. D, J-7Hz, NH)

Comparative Example 84 1) Applying the procedure of Comparative Example 54, (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1 - piperazine carboxamido) is prepared. ) - 3- (S) -formyloxybutanamido) -2-oxoazetidine.

IR κBrcro-1s 3270, 2102, 1772, 1703, 1665, 1510, 1175 max PMH (DMSO-d 6, ppm): 1.11 (t, J = 7H *, CH 3), 1.25 (d, J = 6Hz, CH 3 ), 3.42 (q, J »7Hz, -CH 2 -), 3.58 (in, -CH 2 -), 3.94 (in, -CH 2 -), 4.67 (dd, J * 4.8Hz, *“ ^ H ”), 5.14 (ro.CjH), 5.30 (d, J * 4Hz, C4-H), 5.36 (m, "^ H"), 8.18 (e, CHO), 9.04 (β, ΝΗ), 9.14 (d, J « 8Hz, NH), 9.39 (d, J-8Hz, NH) 2) I By applying the method of Comparative Example 54 • - the corresponding (3S, 4S) -isomer is prepared.

KBr - 1 IR '' max6® 1 3275 '2110' 1782 »171S '167 °» 1515, U80 PMR (DMSO-d6 # ppm) t 1.11 (t, J «7Hz, CH3), 1.23 (d, J = 6Hz , CH3), 3.30% 3.70 (m, -CH2-), 3.42 (q, J * 7Hz, -CH2-), 3.88 ^ 4.08 (m, -CH2-), 4.50 ^ 4.67 (m, C3-H , ~? H “), 5.02 (d, J-1Hz, C4-H), 5.26 ^ 5.52 (m,‘ ^ H “), 8.19 (s, CHO), 8.99 (·, ΝΗ), 9.02 (d, J-8Hz, NH), 9.39 (d, J-8Hz, NH)

Comparative Example 85

By applying the method of Comparative Example 54, ββ 79528 t is prepared from 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-fluorooxoazetidine.

KBr IR cm -1; 1780, 1670, 1540, 1300, 1040 max

Comparative Example 86

By applying the procedure of Comparative Example 70, (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-chloromethylacetamido) -4-methylthio-2-oxoazetidine is prepared.

KB £ IR ^ cm-1; 1750, 1710, 1670, 1510, 1180 max

Comparative Example 87

Following the procedure of Comparative Example 54, (3R, 4R) -4-t-butylthio-3-D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) -formyloxybutanamide) is prepared. -2-oxoazetidine.

IR vKBrcm ”* i 3270, 1765, 1710, 1672, 1512, 1188 max PMR (DMSO-d 6, ppm) i 0.87 (m, CH 3), 1.09 (t, J» = 7Hz, CH 3), 1.25 (d, J -7H2, CH3), 1.77 (m, -CH2-), 2.48 (t, J = 8Hz, -CH2-), 3.42 (q, J-7Hz, -CH2-), 3.60 (m, -CH2-), 3.95 (m, -CH 2 -), 4.74 (dd, J «5.9Hz,»), 4.92 (d, J-5Hz, C 4 -H), 5.26, 8.18 (e, CHO), 8.84 (·, ΝΗ) , 9.10 (d, J-9Hz, NH), 9.45 (d, J * 9Hz, NH)

Comparative Example 88

Applying the procedure of Comparative Example 54, (3S, 4R) -4-azido-3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -3- (S) -formyloxy-butanamido) is prepared. -2-oxoazetidine.

89 79528 and Ή - 1. 326 ° »2ΐ05» i77s »ι? 22» ΐ7 ° 5 »ΐ665» 1518, 1265 PMR (DMSO-d 6, ppm): 3.1 <K3.50 (m, -CH 2 -), 3.60Ό.90 (m, - CH 2 -), 5.19 (m, C 3 -H, C 4 -H), 5.57 (d, J-8H *, ”^ Η ~), 7.37 (m, aroma, Η), 7.55 (β, ΝΗ), 9.00 ( ·, ΝΗ), 9.15 (d, J «8H *, NH), 9.31 (d, J» 8Hz, Nil)

Comparative Example 89 4- (E-2-acetamidovinyl) thio-3- (2- (2-chloroacetamido) -2-methoxyiminoacetamido) -2-oxoazetidine 1) 0.407 g of (3R, 4R) -4-methylsulfonyl-3 -tritylamino-2-oxoazetidine in 10 ml of acetonitrile, and 0.244 g of the silver salt of N-acetyl-cysteamine and 0.75 g of sodium iodide are added to the solution under ice-cooling, followed by vigorous stirring for 5 hours. Insoluble components are removed by filtration and the filtrate is concentrated. The residue is dissolved in ethyl acetate, washed with water, and the solvent is removed by distillation. The residue is purified by silica gel column chromatography (eluent: AcOEt, CHCl 3: 8: 8: 1) to give 0.297 g of 4- (2-acetylamidoethyl) -thio-3-tritylamino-2-oxoazetidine.

KBr IR 0 cm -1; 3250, 1750, 1670, 1615, 1485, 1260. - max 2) Dissolve 0.076 g of the trityl derivative obtained in 1) above in 20 ml of acetone, and add 0.46 g of p- toluenesulfonic acid monohydrate, followed by stirring at room temperature for 40 minutes, the mixture is concentrated, ether is added to the residue to give 3-amino-4- (2-acetamidoethyl) -thio-2-oxoazetidine as a solid, which is added at -70 ° C with stirring. to a suspension of 0.95 g of 2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride and 1.0 g of diethylamine in 20 ml of methylene chloride to which 2 ml of propylene oxide have been added , after which the temperature of the reaction mixture is allowed to gradually rise to room temperature within one hour.

90 79528 t

The reaction mixture is concentrated and insoluble components are removed by filtration. The filtrate is purified by chromatography on a column of silica gel (eluent AcOEt, CHCl 3 and CH 5 OH 8: 8: 1) to give 0.814 g of 4- (E-2-acetamidovinyl) thio-3- (2- (2- chloroacetamido) -2-methoxyiminoacetamido) -2-oxoacetidine.

KB x IR n> cm -1; 3420, 3250, 1766, 1670, 1620, 1542, max 1265, 1045

Ventilation Example 90 (3S, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (ethoxycarbonyl) methoxy-4-methylthio -2-oxoacetidine 1) Dissolve 3.0 g of (3S, 4S) -3-carbobenzoxamido-4-acetoxy-2-oxoazetidine in 25 ml of acetonitrile, and 2.34 g of zinc acetate and 3.4 g of ethyl glycolate are added to the solution, respectively, followed by stirring for 7 hours 65. ..70 ° C.

The solvent is removed by distillation and the residue is dissolved in ethyl acetate, followed by washing with water and concentration. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate and n-hexane 1: 1) to give 0.372 g of (3S, 4R) -3-carbobenzoxamido-4-ethoxycarbonylmethoxy-2-oxoazetidine isomer (A) and 0.604 g of the corresponding , 4S) -isomer (B).

91 79528 (A) IR 3310, 3200, 1785, 1755, 1730, 1700, 1522, 1260 VDr (B) IR vmaxCIB 1 3310 '1790' 1772 '1736 »1690» 1525, 1240, 1112 PMR (DHSO-d6, ppe ) * 1.10 (t, J-7Hz, CH3), 4.15 <q, J «7Hz, -CH2-), 4.20 (e, -CH2-), 4.31 (dd, J« 1,8Hz, C3-H), 5.02 <d, J (1H «, C4-H), 5.05 (e, -CH2-), 7.36 <e, aroma H), 7.96 (d, J (8Bs, NH), β. · 0 (·, ΝΗ )

To a solution of 0.482 g of the (3S, 4S) -isomer (B) obtained in 1) above in 20 ml of tetrahydrofuran is added 0.40 g of palladium-on-carbon, and the mixture is stirred for 30 minutes under a stream of hydrogen. The catalyst is removed by filtration and the filtrate is concentrated to a volume of 3 ml. On the other hand, 0.574 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride and 0.456 g of triethylamine in 20 ml of methylene chloride, the above-mentioned tetrahydrofuran solution, are added with stirring at -70 ° C. , and 2 ml of propylene oxide are added to this suspension, after which the temperature of the reaction mixture is allowed to gradually rise to room temperature within one hour.

The mixture is concentrated, and tetrahydrofuran and saturated aqueous sodium chloride solution are added to the residue. The tetrahydrofuran layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation, and ether is added to the residue to give 0.601 g of (3S, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (ethoxycarbonyl) methoxy-4- methylthio-2-oxoazetidine.

«79528

| TDr. I

I * «3260, 1762, 1660, 1542 PMH (DMSO-d 6, ppro) t 1.08 (t, J = 7Hz, CH 3), 3.66 (q, J« 7Hz, -CH 2 -), 3.91 (*, CH 3), 4.36 (s, -CH2-), 4.52 (dd, J »1.8H *, C3-H), 4.91 (d, J-1Hz, C4-H), 7.39 (β, γΗ), 8.95 (β, ΝΗ ), 9.23 (d, J-8Hz, NH), 12.84 (broad ·, ΝΗ) 2) By applying the method of 1) above, the corresponding (3S, 4R) -isomer is obtained.

KBr IR 0 cnT1; 3260, 1760, 1665, 1555 max

Comparative Example 91 (3S, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -3-methoxy-4-methylthio-2-oxoazetidine

To a solution of 0.612 g of (3S-trans) -3-methoxy-4-methyl-thio-3-p-nitrobenzyloxycarboxamido-2-oxoazetidine in 20 ml of methanol is added 0.9 g of 10% palladium on carbon. carbon (50% moisture content). The mixture is stirred for 50 minutes at room temperature under a stream of hydrogen.

The catalyst is removed by filtration and 0.9 g of 10% palladium on carbon is added to the filtrate, followed by stirring for 50 minutes under a stream of hydrogen.

The catalyst is removed by filtration and the filtrate is concentrated. The concentrate is dissolved in 30 ml of methylene chloride.

On the other hand, to a solution of 1.5 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid in 30 ml of methylene chloride and 1.7 g of pyridine are added with stirring "79528 the methylene chloride solution prepared above and 0, 5 ml of phosphorus oxychloride in this order, while stirring and maintaining the temperature at -30 ° C.

(After 30 minutes, the solvent is removed by distillation, the residue is dissolved in ethyl acetate and washed with water. The solvent is removed by distillation and the residue is purified by silica gel column chromatography (eluent: 1: 5 mixture of CHCl3 and AcOEt) to give 0.384 g (3S, 4R). 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -3-methoxy-4-methylthio-2-oxoazetidine.

IR νΚΒΓαη ”^ ί 3230, 1765, 1670, 1535 max PMF (DMSO-d 6, ppm): 2.20 (s, CH 3), 3.63 (s, CH 3>, 4.05 (e, CH 3), 4.37 (e, ClCH 2 -) , 4.88 (s, C4-H), 7.75 (e, yH) i. Comparative Example 92

Applying the procedure of Comparative Example 70, (3S, 4R) -4-azido-3- (2- (4-ethyl-2,3-dioxopiperazinecarboxamido) -4-pentynamido) -2-oxoacetyl ester is prepared.

PMR (DMSO-d 6, ppm): 1.10 (t, J «7Hz, CH 3 -, 2.71 (m, -CH 2 -), 2.84 (m, HCs), 3.40 (q, J« 7Hz, -CH 2 -), 3.56 (m, -CH 2 -), 3.92 (m, -CH 2 -), 5.10, 5.16 (y. dd, J = 4.8Hz, C 3 - H), 5.30, 5.32 (y. a, J = 4Hz, C 4 - H), 9.06 (m, NH), 9.41 (d, J-8Hz, NH) 1

Comparative Example 93

Following the procedure of Comparative Example 77, 4- (2-acetamidoethyl) thio-3- (D-2- (4-ethyl-2,3-94,79528 dioxo-piperazinecarboxamido) -2-phenylacetamido) -2-oxo-azetidine ( mixture of cis and trans compounds).

KBr - 1 IR vroaxcni! 3280 '1755' 1710 '1670' 1500 '1220' 1180, 1012 PMF (DMSO-d 6, ppm): 1.78, 1.80 (each s, CH 2), 4.55 (dd, J = 2.8Hz, C 3 'H'), 4.64 (d, J = 2Hz, C4-H), 4.86 (d, J * 5Hz, C4-H), 5.28 (m, C3-H), 5.47, 5.63 (each d, 4-8Hz, *? ") “), 9.27, 9.31 (min. D, J = 8Hz, NH), 9.78, 9.82 (jok.-B, J« 8Hz, NH)

Compare reading example 94

Applying the procedure of Comparative Example 70, (3S, 4R) -4-azido-3- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine is prepared.

IR vJ ^ aiT1: 3230, 2102, 1770, 1660, 1540, 1280, 1048

Ju & X

PMR (DMSO-d 6, ppm): 3.91 (e, CH 3), 5.20-5.40 (m, C 3 -H, C 4 -H), 7.40 (s, YH), 8.50 (s, CHO), 9.02 (e, NH ), 9.54 (d, J «8Hz, NH)

Comparative Example 95

Following the procedure of Comparative Example 77, 4- (2-acetamidoethyl) thio-3- (2- (2-chloroacetamidothiazol-4-yl) -2- (2-oxo-3- (thiophene-3-aldoimino) - imidazolidin-1-yl) -karboksamido) acetamido-2-pyrrolidine-oksoatseti.

KBr -1 IR νmaxan * 3290 '176 ° »1720» 1670' 1520 '139 ° »1264, 1220 PMB (DMSO-d 6, ppm): 1.83 (s, CH 3), 4.37 (s, C 1 CH 2 -), 5.49 (d , J = 8Bz, (^ H '), 7.02 (broad S, NH), 7.83, 7.85 (each s # yH) # 7.7i (broad s, NH), 9.0-V9.3 (broad m, NH) 95 79528

Comparative Example 96 (3R, 4R) -4- (2-Acetamidoethyl) thio-3- (2- (2-chloroacetamido-thiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ) -ethoxyimino) -acetamido-2-oxoazetidine In an ice-water cooled solution of 1.8 g of (3R, 4R) -3-amino-4- (2-acetamidoethyl) -thio-2-oxoazetidine p-toluenesulfonate, 1 , 5 g of triethylamine and 10 ml of methylene chloride, a solution of the corresponding acid chloride in 10 ml of methylene chloride is added, the acid chloride being prepared in a manner known per se using 2.2 g of 2- (2-chloroacetamididiazol-4-yl) -2- (1 -methyl-1- (2-trimethylsilyl-ethoxycarbonyl) -ethoxyimino) acetic acid, 1.02 g of phosphorus pentachloride and 35 ml of methylene chloride.

The mixture is stirred for 30 minutes, then concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel (eluent: AcOEt / CH 3 OH 9: 1) to give 0.83 g of (3R, 4R) -4- ( 2-Acetamidoethyl) thio-3- (2- (2-chloroacetamido-thiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino) acetamido-2- oxoazetidine.

IR ν max λmax 1: 1760, 1660, 1545, 860, 840 max PMR (CDCl3, ppm): 1.00 (t, J * = 8Hz, -CH2-), 1.60 (s, CH3), 1.63 (s, CH3 ), 1.95 (s, COCH 3), 2.76 (m, -CH 2 -), 3.60 (m, -CH 2 -), 4.20 (t, J = 8 Hz, -CH 2 -), 4.26 (e, -CH 2 -), 5.03 (d, J = 4Hz, C4-H), 5.60 (dd, J-4.8Hz, C3-H), 7.03 (broad, NH), 7.46 (s, yH), 7.80 (broad, s, NH ), 8.45 (d, J «8Hz, NH)

Comparative Example 97 (3R, 4R) -4-Methylthio-3- (2- (2-tritylaminothiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino) -2-oxoazetidine 96 79528

To 0.915 g of (3R, 4R) -3-amino-4-methylthio-2-oxoacetidine p-toluenesulfonate is added 3 ml of pyridine and stirred for 10 minutes at 25 [deg.] C., then evaporated to dryness under reduced pressure.

On the other hand, a mixture of 1.85 g of (2- (2-tritylaminothiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino) acetic acid is stirred for one hour at 25 ° C. 0.54 g of N-hydroxy-5-norbornene-2,3-dicarboximide, 0.62 g of DCC and 15 ml of methylene chloride To this mixture are added the above-mentioned solid amino derivative, followed by boiling under reflux for 2 hours.

The reaction mixture is filtered and the filtrate is purified by chromatography on a column of silica gel (eluent: 1: 1 mixture of AcOEt and n-hexane) to give 0.66 g of (3R, 4R) -4-methyl, lithio-3- (2- (2-tritylaminothiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino) -2-oxo-azetidine.

KBr —1 IR Vmaxcm! 1775 '1735, 1680, 1620, 1520 PMR (CDCl 3, ppm): 0.03 (s, CH 3), 0.83 (t, J = 8 Hz, -CH 2 -) 1.63 (s, CH 3), 1.70 (s, CH 3), 2.10 (s, SCH3), 4.20 (t, J * 8Hz, -CH2-), 4.96 (d, J * 4Hz, C4-H), 5.66 (dd, J * 4.8Hz, C3-H), 6.60 (ieVeä s, NH), · 6.83 (s, YH), 6.90 (broad s, NH), 7.30 (s, aromrH), 8.06 (d, J-8Hz, NH)

Comparative Example 98

Applying the procedure of Comparative Example 77, a mixture of cis and trans isomers of 3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2-formamidoethyl) thio-2-oxoazetidine is prepared.

97 79528 IR νmaxcra ' ), 4.37 (s, C1CH2-), 4.70 (dd, J <2.8 Hz, C3-H), 4.74 (d, J «2Hz, C4-H), 5.04 (d, J = 5Hz, C4-H) , 5.40 (dd, J <5.8Hz, C, -H), 8.00, 8.10 (each d, J «6Hz, NH), 8.79, 8.81 (each broad '·, ΚΗ), 7.38, 9.46 (each d, J * 8Hz,

Comparative Example 99

Applying the procedure of Comparative Example 89, (3R, 4R) -4- (Z-2-acetamidovinyl) -thio-3- (2- (2-chloroacetamido) -2-methoxyiminoacetamido) -2-oxoacetidine is prepared.

mR <1 IR vmaxc, n: 3260 »1770 'i666» 1542 PMR (DMSO-d 6 ppm): 1.98 (e, CH 3>, 3.88 (s, CH 3), 4.36 (s, -CH 2 -), 5.09 (d , J-4Hz, C4-H), 5.28 (d, J * 8Hz, H u> -), 5.41 <dd, J * 4.8Hz, C, -H), 6.89 (dd, J-8.10Hz, «<"),

B

7.44 (ε, Ύ), 8.85 (s, NH), 9.31 (d, J * 10Rz, NB), 9.44 (d, J «8Hz, NH)

Comparative Example 100

Following the procedure of Comparative Example 77, a mixture of cis- and trans-isomers of 3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2-p-nitrobenzyloxycarbonyl-ethyl) thio-2-oxoazetidine is prepared. .

ι 98,79528 IR VaxCm A: 3255, 2945, 1761, 1690, 1660, 1510, 1345, 1260, 1053, 820 PMR (DMSO-d 6, pprn): 2.6 ^ 2.9 ^, - ^ 2 -), 3.1 ^ 3.4 ( 16, - ^ 2-), 3.88, 3.90 (jok. 8, CH3), 4.37 (8, CICI ^ -), 4.71 (dd, J = 2.8H2, C3-H), 4.73 (d, J «2Hz , C4-H), 5.03 (d, J * 5Hz, C4-H), 5.18 (8, -0 ^), 5.40 (dd, J = 5.8Hz, C3-H), 7.40, 7.48 (6, γΠ ) »7.59, 8.21 (min. D, J = 8Hz, arom, H), 8.77, 8.79 (jok. Leveft s, MH)

Comparative Example 101

Following the procedure of Comparative Example 77, (3R, 4R) -4- (2-acetamidoethyl) -thio-3- (2- (2-formamidothiazol-4-yl) -2- (1-sodiotetrazol-5-yl) -methoxy is prepared. -iminoasetamido) -2-oxoazetidine.

IR vjnaxcn '! 1755 '1660' 1545 * 1290 '1010 PMR (OMSO-d 6, ppm): 1.85 (s, CH 3), 2.86 (in, -CH 2 -), 3.24 (m, -CH 2 -), 4.98 (d, J = 5Hz, C4-H), 5.30 (s, -CH2-), 5.37 (dd, J = 5.8Hz, C3-H), 7.42 (8, ^), 8.32 (t, J = 6Hz, NH), 8.52 (s, CHO), 8.75 (s, NH), 10.00 (d, J = 8Hz, NH) t

Comparative Example 102 (3S, 4R) -4-Azido-3- (2-trimethylsilylethoxycarboxamido) -2-oxoazetidine In an ice-cooled solution of 1.8 g of (3S, 4R) -3-amino-4-azido-2 -oxoazetidine p-toluene sulfonate; 5 ml of methylene chloride; 20 ml of propylene oxide and 0.48 g of pyridine, 1.2 g of 2-trimethylsilylethoxycarbonyl chloride are added. The mixture is stirred for 30 minutes, then concentrated under reduced pressure.

99 7 9 5 2 8

Ethyl acetate is added to the concentrate, and insoluble components are removed by filtration. The filtrate is concentrated and purified by chromatography on a column of silica gel (eluent 1: 1 ethyl acetate / n-hexane) to give 1.085 g of (3S, 4R) -4-azido-3- (2-trimethylsilylethoxycarboxamido) -2-oxoazetidine.

KBx IR V cm-1; 3300, 2100, 1780, 1750, 1700, 1530 max

Comparative Example 103

By applying the method of Comparative Example 97 and using 0.598 g of (3S, 4R) -3-amino-3-azido-2-oxoazetidine tosylate prepared in the same manner as in Comparative Example 45, 0.845 g of (3S, 4R) -4-azido-3- (2- (2-Triethylamino-thiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilyl-ethoxycarbonyl-ethoxyimino) -acetamido-2-oxo-azetidine.

IR νϊΐίαη "1: 3350, 3280, 2112, 1780, 1730, 1675, 1520 max PMR (CDCl 3, ppio) s 0.03 (8, CH 3), 0.97 <t, J« 9Hz, -CH 2 -), 1.95 (S, CH3), 1.97 (s, CH3), 4.21 (t, J * 9Hz, -CH2-), 5.33 (d, J-4Hz, C4-H), 5.56 (αd, J <4.8Hz, C3-H) , 6.75 (s, YH), 6.83 (s, NH), 6.93 (s, ΝΉ), 7.31 (s, arom.H), 8.15 (d, J «8Hz, NH)

Example 1 Sodium (3S, 4S) -4-acetoxy-3-phenoxyacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.45 g of (3S, 4S) -4-acetoxy-3-phenoxyacetamido-2-oxoazetidine in 4 ml of DMF is added 0.515 g of sulfur trioxide and pyridine complex, and the reaction is allowed to proceed continuously. 5 days. 20 ml of diethyl ether are then added and the separated oil is washed with 10 ml of diethyl ether, dissolved in water, treated with "Dowex 50W-Na" resin (Dow Chemical Co) and purified on a column containing XAD resin (Rohm and Haas Co). . 0.462 g of sodium (3S, 4S) -4-acetoxy-3-phenoxyacetamido-2-oxoacetidine-1-sulfonate is thus obtained.

IR vKBrcmwl; 3550, 3250, 1768, 1725, 1635, 1290, 1255, max 1058 PMR (DMSO-d 6, ppm); 2.05 (s, CH 3), 4.54 (s, -CH 2 -), 4.76 (dd, J = 2.9Hz, C 3 -H), 6.21 (d, J = 2Hz, C 4 -H), 6.90-7.44 (m, Aron »H), 9.04 (d, J * 9Hz, NH)

Example 2 Sodium (3S, 4S) -4-acetoxy-3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate (anti-isomer) and syn-isomer

To a solution of 0.586 g of a mixture of syn and anti-isomers of (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 5 ml in DMF1, 0.402 g of a sulfur trioxide-pyridine complex is added and the reaction is allowed to proceed for 7 days. Applying the procedure of Example 1, 0.22 g of sodium (3S, 4S) -4-acetoxy-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfo is obtained. -nat anti-isomer.

IR vKBrcm ”^ | 3450, 3280, 1780, 1750, 1663, 1280, 1245, max 1038 PMR (DMSO-d 6, ppm); 2.04 (s, CH 2), 4.00 (s, CH 3), 4.34 (s, -CH 2 -), 4.74 (dd, J = 2.9 Hz, C 3 -H), 6.23 (d, J = 2 Hz, C 4 H) , 7.93 (8, ^), 9.25 (d, 0 * 9jiz, NH), 12.77 (s, NH) In this way, an additional 0.183 g of syn-isomer is obtained.

ιοί 79528 KRr IR νmax 3425 »3260» 17B0 # 1750, 167 ° f 1260, 1240, 1040 PMR (dg-DMSO, ppm); 2.06 (s, CH3), 3.87 (s, CH3), 4.33 (s, -CH2-), 4.77 (dd, J-2.9Hz, C3-H), 6.10 (d, J = 2Hz, C4-H) , 7.34 (β, 'γ ,!), 9.45 (d, J> 9Hz, NH), 12.87 (s, NH)

Example 3 Syn-Isomer of Sodium (3S, 4S) -4-Acetoxy-3- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.101 g of the above-mentioned sodium (3S, 4S) -4-acetoxy-3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate syn isomer in 4 ml of water, 28.4 g of sodium monomethyldithiocarbamate are added under ice-cooling and stirring, and the mixture is stirred at room temperature for 1 hour. Insoluble components are removed by filtration, and the filtrate is purified on a column containing XAD-II resin. 55.4 mg of sodium (3S, 4S) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate are thus obtained. isomer.

KBr - 1 IR νmaxcm * 3420 · 1785 »177 °» 1735 »16 * 5, 1 ^ 20, 1282, 1245, 1045 PMR (DMSO-d 6, ppm) j 2.05 (s, CH 2), 3.15 (s, CH 3) , 4.71 (dd, J »2.8Hz, C3-H), 6.07 (d, J-2Hz, C4-H), 6.71 (s, ^ fH), 7.13 <e, -NH2), 9.35 (d, J (8Hz, NH)

Example 4 Anti-isomer of sodium (3S, 4S) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of the anti-isomer of 2-oxoazetidine-1-sulfonate of sodium (3S, 4S) -4-acetoxy-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) In 4 ml of water, 29 mg of sodium monomethyldithiocarbamate are added under ice-cooling and stirring, and the mixture is stirred at room temperature for one hour. Insoluble components are removed by filtration and the filtrate is purified on a column of XAD-II resin (Rohm & Haas Co). 48 mg of the anti-isomer of sodium (3S, 4S) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate are thus obtained.

1R v ^ cnf1; 3460, 3350, 1780, 1750, 1730, 1665, 1610, max 1280, 1240, 1040 PMR (DMSO-d 6, ppm); 2.04 (s, CH 2), 3.94 (s, C → 3), 4.73 (dd, J = 2.9Hz, C 3 -H), 6.23 (d, J = 2Hz, C 4 -H), 7.02 (s, -NH 2) ), 7.32 (8, γΗ), 9.18 (d, Js9Hz, NH)

Example 5 Sodium (3R, 4R) -4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine sulfonate

To a solution of 0.18 g of (3R, 4R) -4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine in 3 ml of DMF is added 0.19 g of sulfur trioxide and pyridine complex and the reaction is allowed to proceed for 11 days. Applying the procedure of Example 1, 0.13 g of sodium (3R, 4R) -4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine sulfonate is obtained.

IR νmaxc "1370» 1785 »1685, 1290, 1250, 1058 PMR (DMSO-d6, ppm); 3.16 (e, CH3>, 4.53 (s, -CH2-), 5.16 (d, J <5Hz, C4- H), 5.71 (dd, J <5.10 Hz, C3-H), 6.80-7.43 (m, aroin. M), 8.35 (d, J-10Hz, NH)

Example 6 Pyridinium (3S, 4R) -3-benzyloxycarboxamido-4-methoxy-2-oxoazetidine-1-sulfonate 103 79528

To a solution of 0.2 g of (3S, 4R) -3-benzyloxycarboxamido-4-methoxy-2-oxoazetidine in 3 ml of DMF is added 0.255 g of a sulfur trioxide-pyridine complex and the reaction is allowed to proceed for 4 days. 30 ml of diethyl ether are then added and the oil which has separated is washed with diethyl ether. Crystals are obtained which are washed with ethyl alcohol and collected by filtration. 0.226 g of pyridinium (3S, 4R) -3-benzyloxycarboxamido-4-methoxy-2-oxoacetidine-1-sulfonate is thus obtained; 3180, 1770, 1690, 1250, 1060 PMR (PMSO-d 6, ppm); 3.44 (s, CH3), 4.79 (dd, J = 5.9Hz, C3-H), 5.02 (s, -CH2-), 5.05 (d, J = 5Hz, C4-H), 5.20a broad s, H + N *), 7.33 (s, arom H), 7.90 (d, J * 9Hz, NH), 8.03 (t, J = 7H2, rQU), 8.57 (t, J * 7Hz, 10 -H), 8.90 (d , J = 7Hz,)

Example 7 cis-trans-cis trans isomer of sodium (3S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate mixture

To a solution of the cis-trans mixture of the syn-isomer of (3S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine 3 In 1 ml of DMF, 0.16 g of a complex of sulfur trioxide and pyridine is added and the reaction is allowed to proceed for 30 days. Applying the procedure of Example 1, 0.023 g of sodium (3S) -4-azido-3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate is obtained. isomeric trans mixture of isomer.

104 79528 IR ν cm -1 3420, 3275lolake), 2110, 1775, 1670, max 1275, 1050 (DMSO-d 6, ppm); · 3.88 (s, CH 3), 4.13 (s, -CH 2 -), 4.53 (dd, J <2.8 Hz, trans C3-H), 5.19 (d, J = 2Hz, trans C4-H), 5.19 (dd, J = 4.8Hz, cis C3> H) f 5.42 (d, J = 4Hz, cis C4-H), 7.40 (s, cisv | ('H), 7.43 (s, transy1), 9.45 (d, J = 8Hz, cis NH), 9.48 (d, J * 8Hz, trans NH), 12.70 (s, NH)

Example 8 Syn-isomer of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylsulfonyl-2-oxoacetidine-1-sulfonate

To a solution of 0.233 g of (3R, 4R) -3- (2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4-methylsulfonyl-2-oxoacetidine a mixture of isomers in 3 ml of DMF, 0.18 g of sulfur trioxide and pyridine complex is added and the reaction is allowed to proceed for 22 days. Applying the procedure of Example 1, 0.023 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylsulfonyl-2-oxoacetidine-1- sulfonate syn isomer.

IR v * Brdn "'l | 3450-3400, 1785, 1685, 1672, 1280, 1260,

luaX

1052 (DMSO-d 6, ppm); 3.84 (s, CH3), 4.33 (s, -CH2 “), 5.15 (d, J <5Hz, C4-H), 5.71 (dd, J-5.9Hz, C3-H), 7.53 (β, γΗ) , 9 45 (d, J-9Hz, NH), 12.88 (s, NH)

Further purification by column chromatography gives 0.023 g of anti-isomer.

IP vKBrcra ”^ | 3450-3400, 1785, 1675, 1285, 1260, 1052

l & FTX

PMR (DMSO-d 6, ppm); 3.98 (S, CH 3), 4.33 (s, -CH 2 -), 5.20 (d, J = 6Hz, C 4 -H), 5.78 (dd ', J <6.10Hz, C 3 -H), 7.83 (s, H), B.35 (d, J-10Hz, NH), 12.77 (b, NH) 105 79528

Example 9 Sodium (3R, 4S) -4-ethylthio-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate

To a solution of 0.201 g of (3R, 4S) -4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of DMF is added 0.226 g of a sulfur trioxide-pyridine complex and the reaction is allowed to proceed for 5 days. 0.084 g of sodium (3R, 4S) -4-ethylthio-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate are prepared in the same manner as in Example 1.

IR v ^ cnf1; 3425, 1765, 1670, 1240, 1050 mdx PMR (DMSO-d 6, ppm); 1.18 (t, J = 7Hz, CH 3), 2.62-2.90 (m, -CH 2 -), 4.55 (s, -CH 2 -), 4.70 (dd, J = 3.9 Hz, C 3 -H), 4.94 (d, J-3Hz, C4-H), 6.88-7.44 (m, aroma H), 9.04 (d, J = 9Hz, NH)

Example 10 Sodium (3R, 4R) -4-ethylthio-3-phenoxyacetamido-2-oxoacetidine-1-sulfonate

To a solution of 0.128 g of (3R, 4R) -4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of DMF is added 0.145 g of a sulfur trioxide-pyridine complex and the reaction is allowed to proceed for 4 days. 30 ml of diethyl ether are then added to separate the oil, which is washed with diethyl ether. with ether to form crystals. To a solution of this pyridinium salt in 20 ml of water is added Dowex-50W-Na resin, and the mixture is stirred for 30 minutes. The resin is removed by filtration and the filtrate is lyophilized. 0.115 g of sodium (3R, 4R) -4-ethylthio-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate is thus obtained.

IR ν max ν 3400, 3325, 1760, 1665, 1240, 1058 max PMR (d 6 -DMSO, ppm); 1 * 16 (t, J 7 Hz, CH 2), 2 * 73 (<j, Je 7 Hz) , -CH 2 -), 4.57 (-, CH 2 -), 5.12-5.38 (m, C 3 -H, C 4 -H), 6.88-7.46 (m, aro H), 8.83 (d, J 9 Hz, NH) 106 79528

Example 11 Sodium (3S, 4R) -4-methylsulfinyl-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate

To a solution of 0.30 g of (3S, 4R) -4-methylsulfinyl-3-phenoxyacetamido-2-oxoazetidine in 4 ml of DMF is added 0.338 g of sulfur trioxide-pyridine complex and the reaction is allowed to proceed for 3 days. Applying the procedure of Example 1, 6 mg of sodium (3S, 4R) -4-methylsulfinyl-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate are obtained.

KBir IR ^ cm'1; 3500-3400, 1780, 1765, 1520, 1300-1200, max 1055, 1020

Example 12 Syn Isomer of Disodium (3S, 4S) -4-acetoxy-3- (2- (2-sulfonatoamino-thiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoacetidine-1-sulfonate and an anti-isomer

To a solution of 0.220 g of the syn-isomer of (3S, 4S) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoacetide in 4 ml in DMF, 0.430 g of sulfur trioxide-pyridine complex is added and the reaction is allowed to proceed for 10 days. Applying the procedure of Example 1, the synthesis of disodium (3S, 4S) -4-acetoxy-3- (2- (2-sulfonatoamino-thiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate is obtained. 0.089 g of the isomer and 36.2 mg of the anti-isomer.

Syn-isomer of IR νϊ? ΊοΓ1 | 3450, 3230, 1782, 1665, 1512, 1232, 1045

luAX

PMR. (DMSO-d 6, ppm); 2.08 (s, CH3), 3.87 (s, CH3), 4.75 (dd, J®2, 8Hz, C3-H), 6.09 (d, J «2Hz, C4-H), 6.97 (b, V), 9.46 (d, Js8Hz, NH), 10.00 (broad β, ΗΗ) 107 79528

Anti-isomer IR νmaxcira "" ** 3450 # 3260 '1778 # 1660' 1512 »1228 * 1040 PMR (DMSO-d6, ppm); 2.05 (s, CH3), 3.99 (s, CH3), 4.73 (dd, J = 2.8Hz, C3-H), 6.23 (drJ = 2Hz, C4-H), 7.58 (6, ^), 9.40 (d , J «8Hz, NH) f 9.70 (broad s, NH)

Further purification by column chromatography gives 34.1 mg of the synthesis of sodium (3S, 4S) -4-acetoxy-3- (2- (2-sulfonatoaminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine. isomer. »IR vKBrcm” 1; 3400, 3250, 1775, 1660, 1522, 1230, 1040 max PMR (DMSO-d 6, ppm); 2.09 (s, CH 3), 3.88 (e, CH 3), 4.70 (dd, J = 2.8 Hz, C 3 -H), 5.80 (d, J 3 = 2 Hz, C 4 -H), 6.97. , 9.17 (s, NH), 9.28 (d, Js8Hz, NH), 9.96 (broad s, NH)

Example 13 Sodium (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.432 g of (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetamido) -2-oxoazetidine in 4 ml DMF-. a, 0.318 g of a complex of sulfur trioxide and pyridine is added, and the reaction is allowed to proceed for 10 days. Applying the procedure of Example 1, 0.306 g of sodium (3S, 4S) -4-acetoxy-3- {2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetamido) -2-oxoacetidine-1-sulfonate is obtained.

IR vKBrciif1; 3420, 3270, 1780, 1760, 1668, 1540, 1280- max 1230, 1042 PMR (DMSO-d 6, ppm); 1.22 (d, J * 6Hz, CH 2), 2.06 (s, CH 3), 4.10-4.50 (m, “? H”), 4.36 (e, -CH 2 -), 4.77 (dd, J = 2.8 Hz, C 3 -H), 6.13 (d, J <2 Hz, C4-H), 7.34 (1H, s, ^), 9.33 (d, J «8Hz, NH), 12.80 (broad s, NH) 108 79528 l

Example 14 Sodium (3S, 4S) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.250 g of sodium (3S, 4S) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetamido) -2-oxoazetidine-1-sulfonate in 4 ml: in water, 73 mg of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred for 1 hour at room temperature. Insoluble components are removed by filtration, and the filtrate is purified on an XAD-II column to give 0.153 g of sodium (3S, 4S) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-isopropoxy -iminoasetamido) -2-oksoatseti-pyrrolidine-1-sulfonate.

IR νmaxCin "1; 342 ° -3325 '1785' 1665 '1615' 1515 '1280' 1240, 1068, 1040 PMR (DMSO-d 6, ppm); 1.20 (d, J * = 6Hz, CH 2), 2.06 (s, CH3), 4.2 δ (heptet, J = 6Hz, "<TH"), 4.73 (dd, J = 2.8Hz, C3-H), 6.12 (d, J «2Hz, C4-H), 6.67 (8, ^), 7.14 (s, NH 2>, 9.21 (d, J = 8Hz, NH)

Example 15 Sodium (3S, 4S) -4-acetoxy-3- D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) oxoacetidine-1-sulfonate

To a solution of 0.50 g of (3S, 4S) -4-acetoxy-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) oxoazetidine 1 in 1 ml of DMF, 0.32 g of sulfur trioxide-pyridine complex is added and the reaction is allowed to proceed for 6 days. Applying the procedure of Example 1, 0.19 g of sodium (3S, 4S) -4-acetoxy-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido is obtained. ) -oksoatsetidiini-1-sulfonate.

109 79528 IR vKBrcm? ^ 1780, 1705, 1670, 1510, 1280, 1240, 1180, max 1060. 1040 PMR [d20 (external standard) ppm]; 1.20 (t, J = 7Hz, CH3), 2.20 (s, CH3), 3.50 (q, J = 7Hz, -CH2-), 3.68 <m, -CH2-), 3.98 (m, -CH2-), 4.80 (d, J «2Hz, C3-H), 5.50 {s, 't'), 6.30 (d, J« 2Hz, C4-H), 7.50 (s, aroma H)

Example 16 Sodium (3R, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.415 g of (3R, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylthio-2-oxoacetidine 1.5 in 1 ml of DMF, 0.32 g of sulfur trioxide-pyridine complex is added and the reaction is allowed to proceed for 6 days. Applying the procedure of Example 1, 0.065 g of sodium (3R, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylthio-2- oxoazetidine-l-sulfonate.

IR vKBrcm'1; 1760, 1700, 1665, 1505, 1240, 1045 md x * PMR (DMSO-d 6, ppm); 1.10 (t, J * 6Hz, CH3), 2.02 (s, SCH3), 3.62 (m, -CH2-), 3.90 (m, -CH2-), 4.80 (dd, J = 2.8Hz, C3-H) , 5.42 (d, J-6Hz, "? H_). 5.80 (d, J = 2Hz, C4-H), 7.40 (s, aroma H), 9.18 (d, J = 8Hz, NH), 9.70 (d, J «6Hz, NH)

Example 17 Sodium (3S, 4R) -4-azido-3-D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxo-azetidine-1-sulfonate

To a solution of 0.44 g of (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2- oxoacetidine in 1.5 ml of DMF, 0.4 to 79528 g of sulfur trioxide and pyridine complex are added and the reaction is allowed to proceed for 5 days. Applying the procedure of Example 1, 0.060 g of sodium (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) is obtained. 2-oxoazetidine-l-sulfonate.

IR ν max T 21} 2110, 1780, 1710, 1680, 1515, 1260, 1050 max PMR (DMSO-d 6, ppm); 1.10 (t, J = 6 Hz »CH 2 -), 3.56 (m, -CH 2 -), 3.90 (m, -CH 2 -), 4.44 (dd, J = 2.8 Hz, C 3 -H), 5.10 (d, J = 2Hz, C4-H), 5.44 (d, Jb6Hz,, 7.38 (s, aroin. H), 9.28 (d, J * 8Hz, NH), 9.76 (d, J * = 6Hz, NH)

Example 18 Sodium (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine-1-sulfonate

To a solution of 0.50 g of (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine in 3 ml of DMF is added at -70 ° C a solution of 0.55 g a complex of sulfur trioxide and DMF in 3.75 ml of DMF, and the reaction is allowed to proceed under ice-cooling for 10 hours. Addition of 0.285 g of pyridine and application of the procedure of Example 1 gives 0.481 g of sodium (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine-1-sulfonate.

IR vKBrcm'1J 3380, 1782, 1760, 1710, 1512, 1255, 1070, max 1045 PMR (DMSO-d6, ppm); 2.05 (e, CH 3), 4.45 (dd, J, 9Hz, C 3 H), 5.07 (e, -CH 2 -), 6.13 (d, J 1 Hz, C 4 -H), 7.40 (s, aroma H), 8.21 (d, J = 9Hz, NH)

Example 19 Sodium (3S, 4S) -4-acetoxy-3-phenylacetamido-2-oxo-azetidine-1-sulfonate

To a solution of 0.214 g of (3S, 4S) -4-acetoxy-tert-butyl-dimethylsilyl-3-phenylacetamido-2-oxoazetidine in 3 ml of DMF is added at -70 ° C a solution of 0.175 g a complex of sulfur trioxide and DMF in 1.19 ml of DMF, and ηι 79528 is allowed to proceed at -5 to + 5 ° C for 2 days. Addition of 0.091 g of pyridine and application of the procedure of Example 1 gives 0.163 g of sodium (3S, 4S) -4-acetoxy-3-phenylacetamido-2-oxoacetidine-1-sulfonate.

IR vKBrcm-1; 3450-3370, 1785, 1760, 1662, 1528, 1280, max 1240, 1068, 1043 PMR (DMSO-d 6, ppm); 2.03 (s, CH 3), 3.46 (s, -CH 2 -), 4.63 (dd, J = 2.9 Hz, C 3 -H), 6.10 (d, J = 2 Hz, C 1 H), 7.30 (s, aroma H), 8.96 (d, J * 9Hz, NH)

Example 20 Sodium (3S, 4S) -4-acetoxy-3- (2-bromo-2-phenylacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.156 g of (3S, 4S) -4-acetoxy-tert-butyl-dimethylsilyl-3- (2-bromo-2-phenylacetamido) -2-oxoacetidine in 2 ml of DMF is added -70 At 0 ° C, a solution of 0.105 g of a complex of sulfur trioxide and DMF in 0.71 ml of DMF is allowed to proceed at -5 to + 5 ° C for 2 days. Addition of 0.055 g of pyridine and application of the procedure of Example 1 gives 0.06 g of sodium (3S, 4S) -4-acetoxy-3- (2-bromo-2-phenylacetamido) -2-oxoazetidine-1-sulfonate.

KRr ·] IR maxcm * 3425 '3275' 1785 »1672 '152 °» 128 ° »1235' 1070, 1042 PMR (DMSO-d 6, ppm)? 2.03 (s, CH 3), 4.65, 4.68,> dd, J (1.8 Hz, C 3 -H), 5.60 (i, "? H"), 6.08, 6.13 (y, d, J-1 Hz, C H), 7.26-7.70 (m, arom, H), 9.37 (d, J> 8Hz, NH)

Example 21 Sodium (3S, 4S) -4-acetoxy-3-amino-2-oxoacetidine-1-sulfonate monoacetate

To a solution of 0.10 g of sodium (3S, 4S) -4-acetoxy-3-benzyloxycarboxamido-2-oxoazetidine-1-sulfonate in 12,79528 ml of water is added 0.016 g of acetic acid and 0.05 g of pellet. carbon dioxide, and the mixture is stirred under a stream of hydrogen gas for 40 minutes. 0.060 g of sodium (3S, 4S) -4-acetoxy-3-amino-2-oxoazetidine-1-sulfonate monoacetate are thus obtained.

IR 3450, 3270, 1778, 1740, 1670, 1638, 1238, max 104 2 PMR (DMSO-d 6, ppm); 2.03 (s, CH3), 3.81 (d, J = 1Hz, C.j-H), 5.82 (d, J = 1Hz, C4-H),

Example 22 1 Sodium (3R, 4R) -4- (Benzothiazol-2-yl) dithio-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate

To a solution of 0.70 g of (3R, 4R) -4- (benzothiazol-2-yl) -dithio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of DMF is added 0.8 g of sulfur trioxide and pyridine complex. The reaction is allowed to proceed for 4 days. Applying the procedure of Example 1, 0.61 g of sodium (3R, 4R) -4- (benzothiazol-2-yl) dithio-3-phenoxyacetamido-2-oxoacetidine-1-sulfonate is obtained.

RBr IR 1 cm -1; 1768, 1670, 1520, 1280, 1240, 1052 max

Example 23 Disodium (3S, 4S) -4-acetoxy-3- (2- (benzothiophen-3-yl) -2- (2-oxo-3-sulfonateimidazolidin-1-ylcarboxamido)) - 2-oxoazetidine- 1-sulfonate

To a solution of 0.446 g of (3S, 4S) -4-acetoxy-3- (2- (benzothiophen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido)) -2-oxoacetidine 3 In 1 ml of DMF, a solution of 0.306 g of a complex of sulfur trioxide and DMF in 2.09 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 2 days. Addition of 0.159 g of pyridine and application of the procedure of Example 1 gives 0.141 g of disodium (3S, 4S) -4-aceto-113 79528 toxin-3- (2- (benzothiophen-3-yl) -2- (2-oxo-3 sulfonate action sololidin-1-ylcarboxamido) -2-oxoazetidine-1-sulfonate.

IR vKBrcm ”^; 3275, 1775, 1710, 1660, 1525, 1270-1220, max 1041 PMR (DMSO-d 6, ppm); 2.04 (S, CH 3), 3.62 (m, -CH 2 -), 4.66, 4.70 (min. Dd, J = 2.8Hz, C3-H), 5.84, 5.86 (jok. D, J = 8Ηζ, “ίΗ”) ), 6.03, 6.15 (each d, J * 2Hz, C4-H), 7.30-8.10 (m, arom H), 8.82, 8.91 (eachd, J = 8Hz, NH), 9.27 9.30 (each d, J * = 8 Hz, NH)

In addition, 0.162 g of sodium (3S, 4S) -4-acetoxy-3- (2 -. (Benzothiophen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido)) - 2- oxoazetidine-1-sulfonate.

KBjt IR V * cm-1: 3450, 3310, 1780, 1710, 1668, 1520, 1250, max 1045

Example 24 Disodium (3S) -4-azido-3- (2- (benzothiophen-3-yl) -2- (2-oxo-3-sulfonatoimidazolidin-1-ylcarboxamido)) - 2-oxoazetidine- 1-sulfonate

To a solution of 0.30 g of (3S) -4-azido-3- (2- (benzothiophen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido) -2- oxo-azetidine in 3 ml of DMF, a solution of 0.322 g of a complex of sulfur trioxide and DMF in 2.19 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C 3 days Addition of 0.167 g of pyridine and application of the procedure of Example 1 gives 0.0732 g of disodium (3S) -4-azido-3- (2- (benzothiophen-3-yl) -2- (2-oxo-3- sulfonate imidazolidin-1-ylcarboxamido) -2-oxoazetidine-1-sulfonate.

ΚΒΐ IR ^ cm'1; 3500-3400, 3300, 2103, 1772, 1705, 1658, max 1520, 1260-1225, 1050 114 79528

In addition, 0.056 g of sodium (3S) -4-azido-3- (2- (benzothiophen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido)) - 2-oxoazetidine is obtained. l-sulfonate.

KBr IR y) cm -1; 3275, 2102, 1770, 1660, 1520, 1255, 1048 max

Example 25 Sodium (3S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetamido) -2-oxoacetidine-1-sulfonate

To a solution of 0.349 g of (3S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetamido) -2-oxoazetidine in 3 ml of DMF is added - At 70 ° C, a solution of 0.322 g of a complex of sulfur trioxide and DMF in 2.2 ml of DMF is allowed to proceed at 0 ° C for 2 days. Addition of 0.17 g of pyridine and application of the procedure of Example 1 gives 0.254 g of sodium (3S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetamido) -2 -oksoatsetidiini-l-sulfonate.

1R 3490-3380, 3275, 2120, 1778, 1670, 1542,

Mnax 1275, 1050 PMR (DMSO-d 6, ppm) and 1.25 (d, J-6HZ, CH 2), 4.16 (trans), O J .pu.

4.36 (cis), (jok. A, -CH2-), 4.30-4.50 (m,,), 4.61 (dd, J <2.8Hz, trans C3-H), 5.21 (d, J «2Hz, trans C4 -H), 5.2 3 (dd, J * 4.8Hz, cis Cj-H). 5.48 (d, J = 4Hz, cis C4-H), 7.41 (cis), 7.44 (trans), (jok. S, H), 9.34 (trans), 9.38 (cis), (jok. D, J »8Hz , NH), 12.72 (cis), 12.86 (trana), (jok. A, NH)

Example 26 Sodium (3S, 4R) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy-2-oxoacetidine-1-sulfonate 115 79528

To a solution of 0.22 g of (3S, 4R) -3- 2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy-2-oxoazetidine in 2 mL of DMF: a, a solution of 0.24 g of a complex of sulfur trioxide and DMF in 0.95 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 17 days. Addition of 0.109 g of pyridine and application of the procedure of Example 1 gives 0.186 g of sodium (3S, 4R) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy-2-oxoazetidine. 1-suifonaattia.

IR VKBrcni ”1; 3400, 3275, 1780, 1750, 1670, 1540, 1278, ----- max 1250, 1042 PMR (DMSO-d 6, ppm); 3.67 (ABq, J = 5.9Hz, -CH 2 -), 3.87 (s, CH 3), 4.36 (s, -CH 2 -), 5.42 (dd, J = 4.9Hz, C 3 -H), 6.37 (d, J = 4Hz, C4 (H), 7.25 (s, arom H), 7.30 (s, V *) <9.42 (d, J = 9Hz, NH), 12.86 (s, NH)

Example 27 Sodium (3S, 4R) -3-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy-2-oxoazetidine-1-sulfonate

To a solution of 0.10 g of sodium (3S, 4R) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy-2-oxoazetidine-1-yl sulfonate in 7 ml of water, 0.027 g of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred at room temperature for 1.5 hours. Insoluble components are removed by filtration, and the filtrate is purified on an XAD-II column to give 0.044 g of sodium (3S, 4R) -3-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylacetoxy -2-oxoazetidine-1-sulfonate.

ne 79528 ι IR vKBrcro "X; 3420, 3320, 1790, 1740, 1663, 1522, 1275, max 1248, 1048 PMR (DMSO-d 6, ppm) i * 3.87 (ABq, J = 11.14H * - - CH 2" ) * 3.92 <8, CH3>, 5.38 (dd, J <4.9Hz, C3-H), 6.34 (d, J = 4Hz, C4-H), 6.58 (8, V *), 7.15 (8, NH ), 7.25 (e, arom. H), 9.32 (d, J = 9Hz, NH)

Example 28 Sodium (3R, 4R) -4-acetylthio-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate

To a solution of 0.294 g of (3R, 4R) -4-acetylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of DMF is added at -70 ° C a solution of 0.459 g of sulfur trioxide and The DMF complex in 3.12 ml of DMF, and the reaction is allowed to proceed at 0 ° C for 2 days. 0.24 g of pyridine and then 20 ml of ether are added to the reaction mixture, and the oily substance which separates is washed twice with ether, after which ethanol is added. The formed crystals (pyridinium salt) are collected by filtration. The crystals are suspended in water, and the suspension is treated with Dowex-50W-Na resin (Dow & Chemicals). The filtrate is lyophilized to give 0.326 g of sodium (3R, 4R) -4-acetylthio-3-phenoxyacetamido-2-oxoazetidine-1-sulfonate.

IR VmaxCm ”1; 3390 * 1770 * 1690, 1522, 1240, 1052 PMR (DMSO-d 6, ppm) and 2.27 (b, CH 3), 4.54 (e, -CH 2 -), 5.28 (dd, J = 5.9 Hz, C 3 -H) , 5.70 (d, J * 5Hz, C4-H), 6.85-7.47 (m, aroin H), 8.90 (d, J * 9Hz, NH)

Example 29 Sodium (3R, 4R) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoacetidine-1- sulfonate 117 79528

To a solution of 0.267 g of (3R, 4R) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoacetidine in 3 ml: DMF, a solution of 0.26 g of a complex of sulfur trioxide and DMF in 1.81 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C for 2 days. By adding 0.138 g of pyridine. and applying the procedure of Example 1, 0.302 g of sodium (3R, 4R) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2 -oksoatse-via amination-l-sulfonate.

1R vKUrcn "11l · 3390, 3280, 1768, 1708, 1670, 1 506, 1275, max 1250, 1182, 1045 PMR <DMSO-dfa, ppm); 1.09 (t, J = 7Hz, 1.96 (s, CH_j ), 3.25- 3.70 (m, -CH 2 -), 3.38 (q, J = 7Hz, -CH 2 -), 3.B2-4.00 (m, -CH 2 -), 5.33 (dd, J * 5.8Hz, C3-H), 5.43 (d, J = 7Hz,), 5.49 (d,

Js51iz, C (-H), 7.38 (s, arom. H), 9.20 (d, Je 8Hz, NH), 9.78 (d, J = 7Hz, NH)

Example 30 Sodium (3R, 4S) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2-oxoacetidine-1- sulfonate

To a solution of 0.30 g of (3R, 4S) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2- oxoazetidine in 3 ml of DMF, a solution of 0.248 g of a complex of sulfur trioxide and DMF in 1.69 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.129 g of pyridine and application of the procedure of Example 1 gives 0.305 g of sodium (3R, 4S) -4-acetylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2 phenylacetamido) -2-oksoatseti-pyrrolidine-1-sulfonate.

118 79528 IB vKBrcnT1 »3460, 3280, 1772, 1708, 1675, 1508, 1278, max 1255, 1180, 1048 PMR (DMSO-d 6, ppm); 1.09 (t, J = 7Hz, CH 3), 2.31 (s, CH 3), 3.39 (q, J * 7Hz, -CH 2 -), 3.42-3.70 (m, -CH 2 -), 3.80-4.02 (m, -CH 2 -) -), 4.78 (dd, J <3.8Hz, C3-H), 5.23 (d, J = 3Hz, C.-H), 5.43 (d; j «7Hz,“ 1H ”), 7.38 (s, arom H), 9.38 (d, J «8Hz, NH), 9.75 (d, J« 7Hz, NH)

Example 31 Sodium (3R, 4R) -4-acetylthio-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoacetidine-1-sulfonate

To a solution of 0.25 g of (3R, 4R) -4-acetylthio-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 3 mL of DMF is added - At 70 ° C, a solution of 0.227 g of a complex of sulfur trioxide and DMF in 1.56 ml of DMF is allowed to proceed at 0 ° C for 3 days. Addition of 0.12 g of pyridine and application of the procedure of Example 1 gives 0.208 g of sodium (3R, 4R) -4-acetylthio-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2- oxoazetidine-l-sulfonate.

IR vKBrcm ”1; 3460, 3270, 1770, 1665, 1538, 1260, 1045

lttdX

PMR (DMSO-d 6, ppm); 1.86 (s, CH3), 3.93 (s, CH3), 4.38 (s, -CH2-), 5.34 (dd, J = 5.8Hz, C3-H), 5.87 (d, J = 5Hz, C4-H) ), 7.70 (S, J), 8.65 (d, J = 8Hz, NH), 12.94 (s, NH)

Example 32 Sodium (3R, 4R) -4-acetylthio-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.10 g of sodium (3R, 4R) -4-acetylthio-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate in 5 ml in water, 0.030 g of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred for 3 hours at room temperature. Applying the procedure of Example 3, 0.016 g of sodium (3R, 4R) -4-acetylthio-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfo- carbonate.

KBr IR) cm-1; 3400, 1770, 1668, 1522, 1270, 1245 max 1050

Example 33 Sodium (3R, 4S) -4-acetylthio-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.30 g of (3R, 4S) -4-acetylthio-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 3 ml of DMF, a solution of 0.273 g of a complex of sulfur trioxide and DMF in 1.86 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 2 days. Addition of 0.142 g of pyridine and application of the procedure of Example 1 gives 0.22 g of sodium (3R, 4S) -4-acetylthio-3-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2- oxoazetidine-1-sulfonate.

1R VKBrcm -1; 3480, 3250, 1770, 1670, 1540, 1270, 1045 max 1'MR (DMSO-d6, ppm); 2.37 (s, CH3), 3.89 <s, CH3), 4.36 (s, -C112 -), 4.95 (dd, J * = 2.8Hz, C3-H), 5.33 (d, J = 2Hz, C4-H), 7.44 (S, γ1), 9.54 (d, J = 8Hz, NH), 12.86 (lfveii s, NH)

Example 34 Sodium (3R, 4S) -4-acetylthio-3-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-2-oxoazetidine-1-sulfonate

To a solution of 0.11 g of sodium (3R, 4S) -4-acetylthio-3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate In 5 ml of water, 0.036 g of sodium monomethyldithiocarbamate 120,79528 bamate are added under ice-cooling, and the mixture is stirred at room temperature for 2 hours. Applying the procedure of Example 3, 0.032 g of sodium (3R, 4S) -4-acetylthio-3-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-2-oxoazetidine-1-sulfonate is obtained.

IR vKBrcm "**; 3410, 3315, 1760, 1665, 1515, 1270, 1245, max 1045 · PMR (DMSO-d 6, ppm); 2.36 (s, CH 2), 3.84 (s, CH 2), 4.90 (dd , J = 2.8Hz, C3-H), 5.33 (dfJ = 2HzfC4-H), 6.79 (s, ^), 7.16 (s, NH), 9.42 (d, J = 8Hz, NH)

Example 35 Sodium (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylsulfonyl-2-oxoacetidine-1- sulfonate

To a solution of 0.25 g of (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -4-methylsulfonyl-2-oxoacetidine 3 in ml of DMF, a solution of 0.202 mg of a complex of sulfur trioxide and DMF in 1.38 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 9 days. Addition of 0.158 g of pyridine and application of the procedure of Example 1 gives 0.194 g of sodium (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2- phenylacetamido)) - 4-methyl sulfone-phenyl-2-oxoazetidine-1-sulfonate.

IR ν max T1, 3420, 3290, 1780, 1705, 1670, 1505, 1280, 1252, 1050 PMR (DMSO-d 6, ppm); 1.10 (t, J = 7Hz, CH3), 2.95 (s, CH3) 3.40 (q, J »7Hz, -CH2-), 3.50-3.72 (m, -CH2-), 3.80-4.02 (m, -CH- -), 5.08 (d, J = 5Hz, C.-H), 5.67 (dd, J = 5.9Hz, * —PH— * C3-H), 5.75 (d, J = 7Hz, T) r 7.22- 7.50 (m, arom H), 9.06 (d, J * 9Hz, NH), 9.74 (d, J-7HZ, NH) 121 79528

Example 36 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido)) - 4-methylsulfonyl-2-oxoazetidine-1-sulfonate

To a solution of 0.15 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyacetamido) -4-methylsulfonyl-2-oxoazetidine-1- sulfonate in 5 ml of water, 0.044 g of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred at room temperature for 70 minutes. Applying the procedure of Example 3, 0.078 g of sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido)) - 4-methylsulfonyl-2-oxoazetidine is obtained. -1-sulfonate.

IR 3400, 3325, 1782, 1670, 1612, 1520, 1278, max 1250, 1050 PMR (DMSO-d 6, ppm); 3.16 (s, CH3), 3.82 (s, CH3), 5.16 (d, J <5Hz, C4-H), 5.70 (dd, J »5.8Hz, C3-H), 6.98 (s,, 7.13 (broad)) s, NH 2) * 9.34 (d, J * 8Hz, NH)

Example 37 Sodium (3R, 4S) -4-methylthio-3- (2- (2-methylthioacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoacetidine-1-sulfonate 1

To a solution of 0.341 g of (3R, 4S) -4-methylthio-3- (2- (2-methylthioacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 2 mL of DMF is added -70 ° At C, a solution of 0.400 g of a complex of sulfur trioxide and DMF in 2.7 ml of DMF is allowed to proceed at 0 ° C for 2 days. Addition of 0.206 g of pyridine and application of the procedure of Example 1 gives 0.246 g of sodium (3R, 4S) -4-methylthio-3- (2- (2-methylthioacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine -1-sulfonate.

l 122 79528 IR «V1, 3425, 3250, 1765, 1658, 1540, 1280-1245, 1045 max PMR (DMSO-d6, ppm); 2.17 (b, CH 3>, 2.22 (b, CH 3), 3.38 (8, -CH 2 -), 3.90 (s, OCH 3), 4.62 (d, J * 3Hz, C 4 -H), 4.87 (d, J * 3Hz) , C3-H), 7.38 (8, V1)

Example 38 Sodium (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine-1- sulfonate

To a solution of 0.30 g of (3S, 4R) -4-azido-2- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine 2 In 1 ml of DMF, a solution of 0.307 g of a complex of sulfur trioxide and DMF in 1.18 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 2 days. Addition of 0.164 g of pyridine and application of the procedure of Example 1 gives 0.272 g of sodium (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2- tienyyliasetamido) -2-oxoazetidin-ni-1-sulfonate.

IR v ^ cnf1; 3480, 3280, 2105, 1772, 1708, 1670, 1505,

IRAX

1275, 1242, 1185, 1045 PMR (DMSO-d 6, ppm); 1.09 (t, J = 7Hz, CH 3>, 3.40 (q, J = 7Hz, -CH 2 -), 3.52-3.68 (m, -CH 2 -), 3.86-4.04 (m, -CH 2 -), 4.47 (dd, J * 2.8Hz, C3-H), 5.12 (d, J = 2Hz, C4-H), 5.72 (d, J = 8Hz, "fH"), 6.96-7.54 (m, aroma, H), 9.35 ( d, J * 8Hz, NH), 9.70 (d, Js8Hz, NH)

Example 39 Sodium (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine-1- sulfonate 123 79528

To a solution of 0.25 g of (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) - 2-oxoazetidine in 2 ml of DMF, a solution of 0.263 g of a complex of sulfur trioxide and DMF in 0.99 ml of DMF is added and the reaction is allowed to proceed at 0 ° C for 3 days. Addition of 0.137 g of pyridine and application of the procedure of Example 1 gives 0.224 g of sodium (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2 -tienyyliasetamido) -2-oxoazetidine-1-sulfonate.

IR ν max V 3480, 3275, 2115, 1775, 1710, 1670, 1502, max '1280-1245, 1185, 1048 μg (DMSO-d 6, ppm); 1.09 (t, J = 7Hz »CH 2 -) # 3.42 (q, J * 7Hz, -CH 2 -), 3.50-3.70 (m, -CH 2 -), 3.86-4.04 (m, -CH 2 -), 5.15 (dd , J * 5.8Hz, Cj-H), 5.44 (d, J = 5Hz, C4 »H), 5.85 (d, J» 8Hz, "1H"), 6.94-7.50 (m, aron H), 9.33 ( d, J (8Hz, NH) 9.74 (d, J-8H *, WH)

Example 40 Sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.40 g of (3R, 4S) -3- (2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine in 2 mL of DMF at -70 ° C, a solution of 0.468 g of a complex of sulfur trioxide and DMF in 1.75 ml of DMF is added and the reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.243 g of pyridine and application of the procedure of Example 1 gives 0.206 g of sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine -1-sulfonate.

124 79528 1R vKBrcm "1i 3450, 3250, 1765, 1666, 1540, 1260, 1042 mdx PMR (DMSO-d 6, ppm); 2.22 (S, CH 3), 3.90 (s, OCH 3), 4.34 (s, -CH 2 - ), 4.71 (dd, J-2.8Hz, C3-H), 4.79 (d, J = 2Hz, C4-H), 7.40 (8, y1), 9.48 (d, J * 8Hz, NH), 12.88 ( s, NH)

Example 41 Sodium (3R, 4S) -3-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido 4-methylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.15 g of the above sodium (3R, 4S) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine-1 sulfonate in 4 ml of water, 0.044 g of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred for 1 hour at room temperature. Applying the procedure of Example 3, 0.057 g of sodium (3R, 4S) -3-2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoacetidine-1 sulfonate.

IR v ^ crn-1; 3410, 3320, 1765 »1665 * 1528 '125 ° * 1050 ΧιαΧ PMR (DMSO-dfa, ppm); 2.20 (s, CH3), 3.85 (s, CH3), 4.68 (dd, J = 2.8Hz, C3-H), 4.74 (d, J »2Hz, C4-H), 6.70 (5.5), 7.18 (broad s, NH 2), 9.36 (d, J-8HZ, NH)

Example 42 Sodium (3R, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -4-methylthio-2-oxoazetidine 1-sulfonate

To a solution of 0.25 g of (3R, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -4-methylthio-2-oxoacetidine 2 in ml of DMF, a solution of 0.260 g of a complex of sulfur trioxide and DMF in 0.98 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to continue at 0125 79528 [deg.] C. for 3 days. Addition of 0.136 g of pyridine and application of the procedure of Example 1 gives 0.157 g of sodium (3R, 4S) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -4-methylthio-2-oxo-azetidine-l-sulfonate.

IR vKBrcio ”11 3275, 1765, 1705, 1670, 1502, 1275, 1238, m ex 1188, 1045 PMR (DMSO-d 6, ppm); 1.10 (t, Js7Hz, CH3), 2.15 (s, CH3), 3.40 (q, J-7Hz, -CH2-), 3.48-3.70 (ro, -CH2-), 3.82-4.04 O -CH2-), 4.54-4.73 (m, C3-H, C4-H), S.71 (d, J-7Hz, "), 6.96-7.54 (», eroin.H), 9.40 (d, J * 9Hz, NH), 9.72 (d, J * 7Hz, NH)

Example 43 Sodium (3S, 4R) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.30 g of (3S, 4R) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 2 mL of DMF A solution of 0.355 g of a complex of sulfur trioxide and DMF in 1.33 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.185 g of pyridine and application of the procedure of Example 1 gives 0.269 g of sodium (3S, 4R) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine -1-sulfonate.

IR ν max cm -1 3490, 3250, 2110, 1775, 1667, 1535, 1260, max 1048 PMR (DMSO-d 6, ppm); 3.91 (s, CH 3), 4.36 (s, -CH 2 -), 4.57 ( dd, J »2.8Hz, C3-H), 5.22 (d, J * 2Hz, C4-H), 7.46 (s, V *), 9.46 (d, J * 8Hz, NH), 12.83 (broad s, NH) t 126 79528

Example 44 Sodium (38,48) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.30 g of (3S, 4S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 2 mL of DMF A solution of 0.356 g of a complex of sulfur trioxide and DMF in 1.33 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 2 days. Addition of 0.185 g of pyridine and application of the procedure of Example 1 gives 0.259 g of sodium (3S, 4S) -4-azido-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine -1-sulfonate.

IR νmax1f, 3480, 3250, 2120, 1780, 1675, 1542, 1280, max 1050 PMR (DMSO-d6, ppm); 3.90 (s, CH3), 4.36 (s, -CH2-), 5.22 (dd, J-4.8Hz, C3-H), 5.45 (d, J «4Hz, C4-H), 7.43 (e,, 9.49 (d, J = 8Hz, NH)

Example 45 Sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.454 g of (3R, 4S) -3- (2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine in 2 mL of DMF , a solution of 0.459 g of a complex of sulfur trioxide and DMF in 1.72 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 3 days. Addition of 0.238 g of pyridine and applying the procedure of Example 1 gives 0.355 g of sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine -L-sulfonate.

127 79528 KBr IR y) cm -1; 3460, 3260, 1765, 1662, 1538, max 1265, 1042

Example 46 Sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.15 g of the above sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine 1-sulfonate in 4 ml of water, 0.039 g of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred for 1.5 hours at room temperature. Applying the procedure of Example 3, 0.064 g of sodium (3R, 4S) -3-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-4-phenylthio-2-oxoacetidine-1-sulfonate is obtained.

KBr IR y) cm-1: 3425, 3320, 1768, 1660, 1610, 1522, 1270; max 1245, 1045

Example 47 Sodium (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -4-methylthio-2-oxoacetide , ine

To a solution of 0.440 g of (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -4-methylthio-2-oxoacetidine in 2 ml in DMF, a solution of 0.460 g of a complex of sulfur trioxide and DMF in 3 ml of DMF is added at -70 [deg.] C. and the reaction is allowed to proceed at 0 [deg.] C. for 48 hours. Addition of 0.5 ml of pyridine and applying the procedure of Example 1 gives 0.154 g of sodium (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -4-methylthio-2-oksoatse polypeptide.

128 79528 IR vKBrc »1j 1760, 1705, 1670, 1500, 1240, 1145 max v PMR. (DMSO-d 6, ppm); 1.10 (t, J = 4Hz, CH 3>, 1.93 (s, SCH 3), 3.55 (m, -CH 2 -), 3.90 (m, -CH 2 -), 5.00 (d, J = 4Hz, C 4 -H) , * * 5.26 (dd, J-6.4Hz, C3-H), 5.90 (d, J-4HZ,,), 6.90- 7.53 (m, arom.H), 9.36 (d, J »6Hz, NH) , 9.83 (d, J = 4 Hz, NH)

Example 48 Sodium (3R / 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.470 g of (3R, 4R) -3- 2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine in 2 ml of DMF, a solution of 0.550 complex of sulfur trioxide and DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C for 48 hours. Addition of 0.5 ml of pyridine and applying the procedure of Example 1 gives 0.365 g of sodium (3R, 4R) -3- 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio- 2-oxo-azetidine-1-sulfonate.

IR 'n | i | XCm ~ 1; 17? 5 '1670, 1540, 1260, 1045 PMli (DMSO-d 6, ppm); 2.30 (s, CH 2), 4.01 (s, CH 2), 4.46 (s, 5.26 (d, J = 4H 2, C 4 -H), 5.50 (d, J - 411z, C 1 -C 6),? .65 ( s,> ^)

Example 49 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.250 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine-1- sulfonate in 8 ml of water, 0.078 g of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred at room temperature for 1.5 hours. Applying the procedure of Example 3, 0.052 g of 79528 sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoacetidine-1 is obtained. sulfonate.

IR v ^ cnf1; 1760, 1665, 1615, 1525, 1260, 1045 max PMR (DMSO-d 6 and D 2 O, ppm); 2.30 (s, CH-j), 3.9b (s, -CH 2 -), 5.23 (d, J * 4Hz, C 4 -H), 5.43 (d, J = 4Hz, C 3 -H), 7.03 (s,

Example 50 Sodium (3R, 4R) -3- (3- (2,6-dichlorophenyl) -5-methyl-4-isooxazolylcarboxamido) -4-methylthio-2-oxoazetidine-1-sulfonate

To a solution of 0.500 g of (3R, 4R) -3- (3- (2,6-dichlorophenyl) -5-methyl-4-isooxazolylcarboxamido) -4-methylthio-2-oxoazetidine in 2 ml: DMF, a solution of 0.643 g of a complex of sulfur trioxide and DMF in 2.4 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C for 18 hours. Addition of 0.5 ml of pyridine and applying the procedure of Example 1 gives 0.270 g of sodium (3R, 4R) -3- (3- (2,6-dichlorophenyl) -5-methyl-4-isooxazolylcarboxamido) - 4-methylthio-2-oxo-azetidin-ni-1-sulfonate.

IR vKlircm_1; 1760, 1660, 1595, 1500, 1250 max 1'MH (DMSO-d 6, ppm); 2.16 (S, CH3), 2.75 (s, CH3), 5.02 (d, J-4Hz, C4-H), 5.30 (dd, J = 4.8Hz, C3-H), 7.56 (s, aroma H), 8.74 (d, J = 8Hz, NH)

Example 51 Sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-5-yl) thio-2 -oksoatsetidiini-1-sulfonate

To a solution of 0.558 g of (3R, 4S) -3-2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-5-yl) -thio-2-oxoazetidine in 5 ml of DMF, a solution of 0.268 g of a complex of sulfur trioxide 79528 and DMF in 2.0 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C: in 3 days. Addition of 0.087 g of pyridine and application of the procedure of Example 1 gives 0.443 g of sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl- 1H-tetrazol-5-yl) thio-2-oxoazetidine-1-sulfonate.

IR * KBrcuTli 1795, 1676, 1540, 1285, 104J

nidx -, PMR (DMSO-d 6, ppro); 3.87 (s, CH3), 3.93 (s, CH3), 4.37 (s, -CH2-), 5.42 (dd, J * 2.8H2, C3-H), 6.30 (d, J = 2Hz, C4H) , 7.42 (8, **), 9.65 (d, i3.8Hz, NH)

Example 52 Sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-5-yl) thio-2 -oksoatsetidiini-1-sulfonate

To a solution of 0.300 g of the above sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-5 -yl) thio-2-oxoazetidine-1-sulfonate in 4 ml of water and 4 ml of buffer (pH = 6.56) under ice-cooling are added 0.0689 g of sodium monomethyldithiocarbamate, and the mixture is stirred at room temperature for 2 hours. Applying the procedure of Example 3, 0.106 g of sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-4- (1-methyl-1H-tetrazole-5- yl) thio-2-oxoazetidine-1-sulfonate.

IR VKBrcm ”* | 3320, 1786, 1661, 1608, 1520, 1270, 1045 max * PMR (DMSO-d 6, ppm); 3.83 (s, CH 3), 5.34 (dd, J = 2.8 Hz, C 3 H), 6.31 (d, J * 2 Hz, C 4 -H), 6.74 (8, 1). 7.16 (water, N <2), 9.52 (d, Js8Hz, NH)

Example 53 Sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-5-yl) -thio- 2-oxoacetidine-1-sulfonate m 79528

To a solution of 0.340 g of (3R, 4R) -3- (2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-5-yl ) -thio-2-oxoazetidine in 3 ml of DMF, a solution of 0.268 g of a complex of sulfur trioxide and DMF in 1.27 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C: in 7 days. Addition of 0.176 g of pyridine and application of the procedure of Example 1 gives 0.318 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1- methyl 1H-tetrazol-5-yl) thio-2-oxoazetidine-1-sulfonate.

IR viaxcm ”1; 1778 '1660' 1540 '13Ci °' 1048 PMR (DMSO-d 6, ppm); 3.69 (s, CH3), 3.88 (s, CH3), 4.ibls, -CH2-), 5.69 (dd, J »4.8HZ, C3-H), 6.48 (d, J = 4Hz, C4-H) , 7.23 (8, ^ 1) 9.58 (d, J * 8Hz, NH)

Example 54 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazol-5-yl) -thio- 2-oxoazetidine-1-sulfonate

To a solution of 0.260 g of the above sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazole -5-yl) thio-2-oxoazetidine-1-sulfonate in 20 ml of 50% methanol, 0.0597 g of sodium monomethyldithiocarbamate are added under ice-cooling, and the mixture is stirred at room temperature for 5 hours. Applying the procedure of Example 3, 0.093 g of sodium (3R, 4R) -3- (2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido) -4- (1-methyl-1H-tetrazole) is obtained. -5-yl) thio-2-oxoazetidine-1-sulfonate.

4,132,79528

IR «KUrcm · 1! 3420, 3320, 1786, 1671, 1520, 1285, 1053 max, Q

PM11 (UMSO-d6, ppm) »3.68 (3H, CH3), 3.87 (3H, CH2), 5.68 (dd, J = 4.8Hz, C3-H), 6.42 (8, ^) 4 6.4 6 (d, J = 4Hz, C4 ~ H), 7.12 (broad β, ΝΗ), 9.48 (d, J = 8Hz, ΝΗ)

Example 55 Sodium (3S, 4R) -4-acetoxy-2- (2S) -2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine-1- sulfonate

To a solution of 0.367 g of (3S, 4R) -4-acetoxy-2- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido) -2-oxoazetidine in 2 ml: DMF, a solution of 0.147 g of a complex of sulfur trioxide and DMF in 2.5 ml of DMF is added at -70 ° C and the reaction is allowed to proceed at 0 ° C for 7 days. Addition of 0.195 g of pyridine and application of the procedure of Example 1 gives 0.162 g of sodium (3S, 4R) -4-acetoxy-2-D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido ) -2-oxoazetidine-1-sulfonate.

i IR vKflrcnf1 | 3280, 1780, 1750, 1710, 1668, 1502, 1280, max 1230, 1182, 1042 PMR (DMSO-d 6, ppm); 1.09 (t, J = 7Hz, CH3), 1.71 (s, CH3), 3.39 (q, J = 7Hz, -CH2-), 5.28 (dd, J = 4.9Hz, C3-H), 5.80 (d, J = 8Hz, "? H"), 6.18 (d, J = 4Hz, C4-H), 9.28 (d, J = 9Hz, NH), 9.72 (d, J = 4Hz, C4-H)

Example 56 Sodium (3S, 4R) -4-acetoxy-3-thienylacetamido-2-oxoazetidine-1-sulfonate

To a solution of 0.206 g of (3S, 4R) -4-acetoxy-3-thienylacetamido-2-oxoazetidine in 2 ml of DMF is added, at -70 ° C, a solution of 0.147 g of sulfur trioxide and DMF: n complex in 2.4 ml of DMF, and the reaction is allowed to proceed at 0 133 79528 ° C for 4 days. Addition of 0f182 g of pyridine and applying the procedure of Example 1 gives 0.135 g of sodium (3S, 3R) -4-acetoxy-3-thienylacetamido-2-oxoazetidine-1-sulfonate.

IR νmax "1 '3450' 3350 '1770' 174 ° '1668' 153 ° '129 °' 1240, 1050 PMR (DMSO-d 6, ppm) and 1.96 (S, CH 3), 3.69 (s, -CH 2 -), 5.22 (dd, J-4.9H * fC3-H), 6.21 (d, J = 4Hz, C4-H), 6.82-7.02 (m, aroma H), 7.23-7.44 (m, aroma H), 8.88 ( d, J * 9Hz, NH)

Example 57 Sodium (3S, 4R) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoacetidine-1-sulfonate

To a solution of 0.404 g of (3S, 4R) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 3 mL of DMF is added -70 At 0 ° C, a solution of 0.147 g of a complex of sulfur trioxide and DMF in 3.1 ml of DMF is allowed to proceed at 0 ° C for 7 days. Addition of 0.237 g of pyridine and application of the procedure of Example 1 gives 0.373 g of sodium (3S, 4R) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine -L-sulfonate.

IR ν max ® 327, 1785, 1760, 1675, 1521, 1285, 1240, max '1050 PMR (DMSO-d 6, ppm); 2.02 (δ, CH 3>, 3.89 (S, CH 3), 4.36 (s, -CH 2 -), 5.37 (dd, J * 4.9Hz, C 3 -H), 6.29 (d, J-4Hz, C 4 -H) , 7.30 (8, y1), 9.37 (d, J 9 Hz, NH), 12.8 (broad s, NH) i

Example 58 Sodium (3R, 4R) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate.34 79528

To a solution of 0.187 g of the above-mentioned sodium (3S, 4R) -4-acetoxy-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate 6 In ml of a buffer solution (pH 6.86), 0.048 g of sodium monomethyldithiocarbamate is added under ice-cooling, and the mixture is stirred for 2 hours at room temperature. Applying the procedure of Example 3, 0.078 g of sodium (3R, 4R) -4-acetoxy-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine is obtained. 1-sulfonate.

IR νmax cm -1 * 3420, 3320, 1775, 1668, 1615, 1520, 1280, 1 1240, 1042 PMR (DMSO-d 6, ppm); 2.01 (e, CH 3), 3.84 (e, CH 3), 5.34 ( dd, J (4.9Hz, C3-H), 6.26 (d, J * 4Hz, C4-H), 6.58 (8, ^), 7.15 (levefi, NH), 9.29 (d, J * 9Hz, NH)

Example 59 Sodium (3S, 4S) -4-acetoxy-3-phenylacetamido-2-oxoazetidine-1-sulfonate

To a solution of 0.61 g of sodium (3S, 4S) -4-acetoxy-3-amino-2-oxoazetidine-1-sulfonate acetate obtained in Example 21 in 20 ml of water and THF 1: 1 mixture, 0.61 g of phenylacetyl chloride is added under ice-cooling, keeping the pH of the reaction mixture in the range of 7.0 to 7.5 with sodium hydrogen carbonate. Stirring is continued for 1.5 hours at the same temperature. The THF is removed by evaporation under reduced pressure. The residue is purified by chromatography on an XAD-II column (Rohm & Haas Co) to give 0.42 g of sodium (3S, 4S) -4-acetoxy-3-phenylacetamido-2-oxoazetidine-1-sulfonate. The IR spectrum and PMR data of this compound correspond to the values of the compound obtained according to Example 19.

Example 60 Disodium (3S, 4R) -3- (2 - ((2-aminothiazol-4-yl) carboxylatomethyliminooxy) -2-methylpropionamido) -4-azido-2-azetidinone-1- sulfonate 135 79528 1) To a solution of 0.625 g of (3S, 4R) -4-azido-3- (2 - ((2-tritylaminothiazol-4-yl) carboxymethyliminooxy) -2-methylpropionamido ) -2-azetidinone in 4 ml of DMF, a solution of 0.459 g of a complex of sulfur trioxide and DMF in 1.8 ml of DMF is added and the reaction is allowed to proceed at 0 ° C for 2 days. 0.238 g of pyridine is added to the reaction mixture, and the mixture is washed with ether. The residue is dissolved in 50% ethanol, and 0.504 g of sodium hydrogencarbonate is added under ice-cooling, followed by stirring for 30 minutes. The ethanol is removed by distillation, and the residue is purified by XAD-II column chromatography to give 0.181 g of disodium (3S, 4R) -4-azido-3- (2 - ((2-tritylaminothiazol-4-yl)). karboksilaattometyyli-imino-oxy) -2-methylpropionamido) -2-azetidinone-1-sulfonate.

IR vKBrce'Xj 3390, 2105, 1770, 1615, 1520, 1270, max 1245. 1045 PMR (DMSO-d 6, ppm); 1.58 (s, CH3), 1.65 (s, CH3), 4.46 (d, J <2 Hs, C3-H), 5.43 (d, J-2Hz, C4-H), 6.63 (b, YH), 7.00- 7.50 (m, aroin H) 2) To a solution of 0.560 g of disodium (3S, 4R) -4-azido-3- (2 - ((2-tritylaminothiazol-4-yl) carboxylate methylimino) -oxy) -2-methylpropionamido) -2-azetidinone-1-sulfonate in 15 ml of 50% ethanol, 0.84 ml of N-HCl are added under ice-cooling, and the mixture is stirred at room temperature for 2.5 hours. 0.070 g of sodium hydrogen carbonate are added under ice-cooling, the mixture is stirred for 20 minutes, after which the ethanol is removed by distillation. Insoluble components are removed by filtration, and the filtrate is purified by XAD-II column chromatography to give 0.067 g of disodium (3S, 4R) -3- (2 - ((2-aminothiazol-4-yl) carboxylate methyliminooxy). ) -2-methylpropionamido) -4-azido-2-azetidinone-1-sulfonate.

136 79528 IR vKBrcm? 2: 3390, 2115, 1775, 1605, 1512, 1270, max 1240. 1048 PMR (DMSO-d 6, ppm); 1.67 (s, CH 3), 4.70 (d, J = 2Hz, C 3 -H), 5.80 (d, J = 2Hz, C 4 -H), 7.09 (8, YH)

Example 61 Disodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamido-4-methylthio-2-azetidinone 1-Sulfonate 1) To a solution of 0.40 g of (3R, 4R) -3- (2- (1- (2-trimethylsilylethoxycarbonyl) -1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl ) acetamido) -4-methylthio-2-azetidinone in 2 ml of DMF, 0.80 g of tetra-n-butylammonium fluoride are added and the mixture is stirred at room temperature for 30 minutes. The DMF is removed by distillation, and the residue is dissolved in ethyl acetate and washed with water. The solvent is removed by distillation to give 0.400 g of (3R, 4R) -3- (2- (1-carboxy-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido) -4- the tetra-n-butylammonium salt of methylthio-2-azetidinone. This product is dissolved in 2 ml of DMF, and a solution of 0.511 g of a complex of sulfur trioxide and DMF in 2 ml of DMF is added at -70 [deg.] C., after which the reaction is allowed to proceed at 0 [deg.] C. in 2 days. .

Addition of 0.5 ml of pyridine and applying the procedure of Example 1 gives 0.150 g of sodium (3R, 4R) -3- (2- (1-carboxy-1-methylethoxyimino) -2- (2-tritylaminothiazol-4 -yl) acetamido) -4-methylthio-2-azetidinone-l-sulfonate. KBr IR 0 cm-1; 1760, 1660, 1610, 1525, 1250 max 2) To a solution of 0.188 g of sodium (3R, 4R) -3- (2- (1-carboxy-1-methylethoxyimino) -2- (2-tritylaminothiazole) 4-yl) -acetamido) 4-methylthio-2-azetidinone-1-sulfonate in 15 ml of 50% methanol, 1.0 ml of N-HCl are added under ice-cooling, and the mixture is stirred at room temperature 137 79528 for 2 hours. Applying the procedure of Example 60, item 2), 0.31 g of disodium (3R, 4R) -3- (2- (2-amino-thiazol-4-yl) -2- (1-carboxylate-1-methylethoxy) is obtained. imino) acetamido-4-methylthio-2-azetidinone-l-sulfonate.

KBr IR0 cm -1; 1760, 1675, 1600, 1250, 1050 max

Example 62 Sodium (3S, 4S) -4-azido-3- (D-2-ureido-2-thienylacetamido) -2-o'-oxoazetidine-1-sulfonate (A) and disodium (3S, 4S) -4 -azido-3- (D-2-3-sulfonate-ureido) -2-thienylacetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.40 g of (3S, 4R) -4-azido-3- (D-2-ureido-2-thienylacetamido) -2-oxoazetidine in 3 ml of DMF is added a solution at -20 ° C, with 0.594 g of a complex of sulfur trioxide and DMF in 2.2 ml of DMF. The reaction is allowed to proceed at 0 ° C for 2 days. 0.307 g of pyridine is added to the reaction mixture, followed by purification according to Example 1 to give 0.131 g of sodium (3S, 4S) -4-azido-3- (D-2-ureido-2-thienylacetamido) -2-oxoazetidine-1-sulfonate ( A) and 0.198 g of disodium (3S, 4S) -4-azido-3-. ((D-2- (3-sulfonate-ureido) -2-thienylacetamido) -2-oxoazetidine-1-sulfonate (B).

... | (A) 1R »*** cm -1: 3315, 2120, 1770, 1660, 1520, 1240, ..... λπα 1050 PMH (DMSO-d 2, ppm): 5.25 (d, J = 5Hz, C , -H), 5.54 (d, J = 5Hz, C4-H), 5.76 (s,,>, 7.03-7.67 (m, aroin, H) (B) 1R »ZZZ cm-1: 3320, 2120, 1775 , 1665, 1520, 1242, ΧιαΧ 1050 PMR (DMSO-d 6, ppm): 5.26 (d, J = 5Hz, C 4 -H), 5.56 (d, J = 5Hz, C 4 -H), 5.76 (s, H "), 7.05-7.63 (m, arom H) 138 138528

Example 63 Sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-oxoazetidine-1-sulfonate 1) In solution, with 0.485 g of (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-oxoazetidine in 2 ml of DMF is added At -70 ° C, a solution of 0.495 g of a complex of sulfur dioxide and DMF in 1.85 ml of DMF. The reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.256 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.430 g of sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio- 2-oxoazetidine-1-sulfonate.

1 R cm -1: 2330, 1763, 1742, 1665, 1540, 1273, 1040 PMR (DMSO-d 6, ppm) ·: 3.67 (s, CH 3), 3.74 (ABq, J = 16 Hz, S-CH 2 -), 3.93 (s, CH 2), 4.37 (s, C fc CH 2 -), 4.74 (dd

Ji.2, 8Hz, Cj-H), 5.01 (d, J * 2Hz, C4-H), 7.40 (s, ^), 9.49 (d, J * 8Hz, NH) 2) To a solution of 0.273 g of sodium - (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-oxoazetidine-1-sulfonate in 6 ml of buffer solution (pH = 6, 86) 67.8 mg of sodium monomethyldithiocarbamate are added under ice-cooling. After stirring for 2 hours at room temperature, purification as described in Example 3 gives 0.120 g of sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethyl spore. - 2-oxo-ethidine-1-sulfonate.

1R v cm -1: 342 ° »3320» 1763, 3722 »1661, 1610, 1520, ΔιαΧ 1275, 1043 PMR (DMSO-d 6, ppm): 3.66 (s, CH 2), 3.72 (ABq, J * 16Hz, S -CH2-), 3.86 (s, CH3), 4.67 (dd, J = 2, 8Hz, C, -H), 4.98 (d, J «2Hz, C4-H), 6.70 (β, γΗ), 7.16 ( broad s, NH 2), 9.36 (d, J-8HZ, NH) 139,79528

Example 64 Sodium (3R, 4R) -4- (E-2-acetamidovinyl) thio-3- (2- (2-chloroacetamido) -2-methoxyiminoacetamido) -2-oxoacetidine-1-sulfonate

To a solution of 0.74 g of 4- (E-2-acetamidovinyl) -thio-3- (2- (2-chloroacetamido) -2-methoxyiminoacetamido) -2-oxoacetidine in 4 ml of DMF , a solution of 0.734 g of a complex of sulfur trioxide and DMF in 2.88 ml of DMF is added at -20 ° C. The mixture is allowed to stand at 0 ° C for 2 days. Addition of 0.38 g of pyridine to the reaction mixture and purification as described in Example 1 gives 0.157 g of sodium (3R, 4R) -4- (E-2-acetamidovinyl) -thio-3- 2- (2-chloroacetamido) '- 2-methoxy -iminoacetamido) -2-oxoacetidine-1-sulfonate.

KBr IRj cm-1; 1766, 1670, 1620, 1542, 1265, 1045 max

Example 65 Sodium (3S-cis) -3-benzyloxycarboxamido-4-ethoxy-3-methoxy-2-azetidinone-1-sulfonate

To a solution of 0.138 g of (3S-cis) -3-benzyloxycarboxamido-4-ethoxy-3-methoxy-2-azetidinone in 1.5 ml of DMF is added at -70 ° C a solution of 0.230 g of a complex of sulfur trioxide and DMF in 0.86 ml of DMF. The reaction is allowed to proceed at 0 ° C for 4 days. Addition of 0.12 ml of pyridine to the reaction mixture and purification as described in Example 1 gives 0.088 g of sodium (3S-cis) -3-benzyloxycarboxamido-4-ethoxy-3-methoxy-2-azetidinone-1-sulfonate.

) R cm-1 and 3390, 1775, 1715, 1490, 1250, 1050 1 H-NMR (DMSO-d 6, ppm): 1.03 (t, J = 711z, CH 2), 3. 14 (r., CH-j), 4.91 ( s, C 4 -H 2, 5.07 (AUq, -Cl 2 -), 7.37 (s, arin. 11), 8.12 (s, NH) 140 79528

Example 66 Sodium (3S-trans) -3-methoxy-4-methylthio-3-p-nitrobenzyloxycarboxamido-2-azetidinone-1-sulfonate

To a solution of 0.161 g of (3S-trans) -3-methoxy-4-methyl-thio-3-p-nitrobenzyloxycarboxamido-2-azetidinone in 1.5 ml of DMF is added at -70 ° C a solution of 0.230 g of a complex of sulfur trioxide and DMF in 0.86 ml of DMF. The reaction is allowed to proceed at 0 ° C for 4 days. Addition of 0.12 ml of pyridine to the reaction mixture and purification according to Example 1 gives 0.138 g of sodium (3S-trans) -3-methoxy-4-methylthio-3-p-nitrobenzyloxycarboxamido-2-azetidinone-1-sulfonate.

1R en »*” 1 s 1770f 1720, 1515, 1350, 1280, 1250, 1050 PMR (DMSO-d 6, ppm): 2.17 (s, CH 2), 3.41. (s, CH 2 -), 4.77 (s, CH 2 -H), 5.22 (s, -CH 2 -). 7.66 and 8.23 (each. D, j = 8Hz, aroma H), 8.48 (s, NH)

Example 67 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-azetidinone-1-sulfonate 1) To a solution in which is 0.405 g of (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-azetidinone in 2 ml of DMF, a solution of 0.416 g of a complex of sulfur trioxide and DMF in 1.5 ml of DMF is added at -70 ° C. The reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.427 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.120 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio -2-azetidinone-l-sulfonate.

141 79528] R KBr cm -1: 3460. 3260, 1778, 1729, 1660, 1540, 1270, max 1040 »Ml * (DMSO-d 6, ppm): 3.61, 3.84 (ABq, J = 1511z, -CH ^ -), 3.64 (s, CH 3), 3.88 (s, CH 3), 4.35 <s, CtCH 2 -), 5.36 (d, J * 5Hz, C 4 -H), 5.37 (dd, J = 5.8Hz, C3-H), 7.49 (s,>, fH), 9.53 (d, J = 8Hz, NH) 2) To a suspension of 0.315 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazole) 4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-azetidinone-1-sulfonate in 10 ml of 50% methanol, 0.074 g of sodium monomethyldiithiocarbamate are added under ice-cooling, and the mixture is stirred at room temperature for 4 hours. Purification of the reaction mixture as described in Example 3 gave 87 mg of sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methoxycarbonylmethylthio-2-azetidinone-1-sulfonate. .

KBr -1 1R max cm-8 3420 '3310' 1767 '1728' 1665 '1612' 1525 '1270, 1048 PMR (DMSO-d 6, ppm): 3.60, 3.84 (ABq, J * 15Hz, -SCH 2 -), 3.65 ( s, CH3), 3.84 (S, CH3>, 5.28 (d, J = 5Hz, C4-H), 5.88 (dd, J <5.8Hz, C3-H), 6.85 (s, γΗ), 7.13 (broad s, NH2), 9.42 (d, J «8Hz, NH)

Example 68 Sodium (3R, 4S) -3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -4-phenylthio-2-azetidinone-1-sulfonate and Disodium (3R, 4S) -3- (D-2- (2-oxo-3-sulfonate-thoimidazolidin-1-yl) -carboxamido) -2-phenylacetamido) -4-phenylthio-2-azetidinone-1 sulfonate

To a solution of 0.40 g of (3R, 4S) -3- (D-2- (2-oxoimidazolidin-1-yl-carboxamido-2-phenylacetamido) -4-phenylthio-2-azetidinone in 3 ml DMF, a solution of 0.28 g of a complex of sulfur trioxide and DMF in 1.04 ml of DMF is added at -70 [deg.] C. The reaction is allowed to proceed at 0 [deg.] C. 2 Addition of 0.144 g of pyridine to the reaction mixture and purification as described in Example 1 gives 0.243 g of sodium (3R, 4S) -3- (D-2- (2-oxo-3-sulfonatoimidazolidin-1-yl) -carboxamido-2 phenylacetamido) -4-phenylthio-2-azetidinone-l-sulfonate.

1R vKBr cm -1: 3280, 1765, 1715, 1665, 1528, 1262, 1050 PMR (DMSO-d 6, ppm): 3.24-3.46 (m, -CH 2 -), 3.64-3.90 (tn, -CH 2 -), 4.54 (d, J <2 Hz, Cj-H), 4.86 (d, J * 2Hz, C4> H), 5.36 (s, "^ H"), 7.36 (s, aroin, H), 7.37 (s, aromaH ) 2) In addition, 0.119 g of disodium (3R, 4S) -3 - ((D-2- (2-oxo-3-sulfonate-imidazolidin-1-yl) -carboxamido-2-phenylacetamido) -4- phenylthio-2-azetidinone-l-thia-sulfone.

1R \> KBr cm -1: 3450, 3305, 1765, 1715, 1668, 1525, J255, nidx 1050 PMR (PMSO-d 6, ppm): 3.20-3.44 (ni, -Cfl 2 -), 3.54-3.84 (m , -C11-), 4.45 (dd, J-2, 9Hz, CjH), 4.83 (d, J = 2Hz, C4-H), 5.36 (d, J = 8Hz,, 7.20-7.60 (m, aroin H) , 7.36 (s, aroma, H), 9.02 (d, J = 8Hz, Nil), 9.31 (d, J = 9Hz, NH)

Example 69 Sodium (3S, 4R) -4-azido-3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -2-azetidinone-1-sulfonate and disodium (3S, 4R) -4-Azido-3- (D-2- (2-oxo-3-sulfonateimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -2-azetidinone-1-sulfonate

To a solution of 0.40 g of (3S, 4R) -4-azido-3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -2-azetidinone 4 in ml of DMF, a solution of 0.337 g of a complex of sulfur trioxide and DMF in 1.26 ml of DMF is added at -70 ° C. The reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.175 g of pyridine to the reaction mixture and purification as described in Example 1 gives 143,78528 of 0.186 g of sodium (3S, 4R) -4-azido-3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido)). -2-phenyl-acetamido) -2-azetidinone-ni-1-sulfonate.

IR >> KBr cm -1: 3290, 2115, 1775, 1715, 1662, 1522, 1270, max 1050 PVTR (DMSO-d 6, ppm): 3.16 * 3.48 (m, -CH 2 -), 3.58 * 3.86 (m, -CH0-), 4.41 (dd, J = 2, 8Hz, C ..- H), 5.09 <d, J = 2Hz, C4-H), 5.39 (d, J = 7Hz, 7 "), 7.36 (s , aroin H), 7.55 (s, NH), 9.02 (d, J * 7Hz, NH), 9.21 (d, J = 7Hz, NH) 2) In addition, 0.111 g of disodium (3S, 4R) -4-azido -3- (D-2- (2-Oxo-3-sulfonateimidazolidin-1-yl-carboxamido) -2-phenyl-acetamido) -2-azetidinone-1-sulfonate.

1R * KBr cm -1: 3460, 3300, 2120, 1765, 1708, 1663, 1522, max 1255, 1052 PMR (DMSO-d 6, ppm): 3.2 (1 * 3.44 (m, -CH 2 *), 3.57 * 3.80 (m, -CH--), 4.42 (dd, J-2.8 Hz, C-H), 5.11 (d, J-2Hz, * -PH-C4-H), 5.39 (d, J = 7Hz,,), 7.36 (s, aron H), 9.02 (d, J = 7Hz, NH), 9.21 (d, J = 8Hz, NH)

Example 70 Sodium (3S-trans) -3- (D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -3-methoxy-4-methylthio-2-azetidinone l-sulfonate

To a solution of 0.16 g of (3S-trans) -3- (D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -3-methoxy-4 -methylthio-2-azetidinone in 1.5 ml of DMF, a solution of 0.142 g of a complex of sulfur dioxide and DMF in 0.53 ml of DMF is added at -70 ° C. In C for 2 days. Addition of 0.075 ml of pyridine to the reaction mixture and purification as described in Example 1 gives 0.115 g of sodium (3S-trans) -3- (D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido ) -3-methoxy-4-methylthio-2-azetidinone-1-sulfonate.

144 79528 1R VKBr cm -1: 3275, 2925, 1770, 1705, 1665, 1500, 1250, max 1050

PMR (DMSO-d 6, ppm): 1.92 (s, CH-), 3.26 (s, CH-), 4.73 (s, b -CH- J

C4-H), 5.60 (d, J * 7Hz,,), 7.2-7.6 (m, arom H), 9.22 (s, NH), 9.78 (d, J * 7Hz, NH)

Example 71 Sodium (3S, 4R) -4-azido-3- (D-2- (3-methyl-3- (methylcarbamoyl) -1-ureido) -2-phenylacetamido) -2-azetidinone-1-sulfonate

To a solution of 0.35 g of (3S, 4R) -4-azido-3- (D-2- (S-methyl-S- (methylcarbamoyl) -1-ureido) -2-phenylacetamido) -2- azetidinone in 3 ml of DMF, a solution of 0.429 g of a complex of sulfur trioxide and DMF in 1.6 ml of DMF is added at -70 ° C. The reaction is allowed to proceed at 0 ° C for 2 days. Adding 0.222 g of pyridine to the reaction mixture and purifying as described in Example 1 gives 0.22 g of sodium (3S, 4R) -4-azido-3- (D-2- (3-methyl-3- (methylcarbamoyl) -1-). ureido) -2-phenylacetamido) -2-azetidinone-1-sulfonate.

1R, KBr cm -1: 3380, 2120, 1778, 1678, 1676, 1502, 1250, max 1050 PMR (DMSO-d 6, ppm): 2.67 (d, J = 4Hz, CH 3), 3.09 (s, CH- j), 4.42, 4.46 (min. dd, J = 2.8 Hz, C, -H), 5.09, 5.13 (jok.

3 .pii.

d, J * 2Hz, C4-H), 5.35 (d, J = 8Hz, j), 7.36 (s, aroma H), 9.17 (d, J = 8Hz, NH), 9.89 <d, J = 8Hz, NH )

Example 72 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyimino, noacetamido) -4-n-butylthio-2-azetidinone -1-sulfonate

To a solution of 0.36 g of (3R, 4R) -4-n-butylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone in 4 ml: in DMF, a solution of 0.381 g of a complex of sulfur trioxide and DMF in 1.43 ml of DMF is added at -70 ° C. The reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.198 g of pyridine to the reaction mixture and purification as described in Example 6 gives 0.445 g of pyridinium- (3R, 4R) -4-n-butylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido ) -2-azetidinone-1-sulfonate.

1R V cm -1: 3250, 1775, 1660, 1550-1530, 1270, 1245, nidx 1208, 1036 PMR (DMSO-d 6, ppm): 0.86 (m, CH 2), 1.43 (m, 2.76 (t, J * 7Hz, -CH2-), 3.86 (s, CH3-), 4.32 (s, -CH2-), 5.13 (d, J = 6Hz, C4-H), 5.34 (dd, J = 6.9Hz, Cj- H), 7.50 (s, YH), 7.97-9.00 (m, arom H), 9.48 (d, J = 9Hz, NH) 2) To a mixture of 0.33 g of pyridinium- (3R, 4R) -4- n-butyl lithio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone-1-sulfonate, 10 ml Dowex 50W resin (Na + form) and 15 ml of 50% ethanol, stirred for 30 minutes, the resin is removed by filtration and the filtrate is lyophilized to give 0.215 g of sodium (3R, 4R) -4-n-butylthio-3- (2- (2-chloroacetamidothiazol-4-yl)). -2-methoxy-iminoacetamido) -2-azetidinone-l-sulfonate.

1R VKBr cm -1 1 3270, 1792, 1656, 1550-1525, 1248, 1050, max 1036 PMR (DMSO-d 6, ppm): 0.87 (m, CH 2), 1.45 (m, -CH 2 -), 2.76 ( t, J = 7Hz, -CH 2 "), 3.88 (s, CH 3), 4.34 (s, -CH 2"), 5.16 (d, J * 6Hz, C 4 -H), 5.35 (dd, J = 6.9Hz, C (-H), 7.51 (s, yH), 9.51 (d, J * 9Hz, NH), 12.93 (broad S, NH) (3) To a solution of 0.17 g of sodium (3R, 4R) - 4-n-Butylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone-1-sulfonate in 16 ml of 50% ethanol is added on ice cooling 0.053 g of sodium monomethyldithiocarbamate. After stirring for 50 minutes at room temperature, the ethanol is removed under reduced pressure. The residue is purified on an XAD-11 column to give 0.064 g of sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-n-butylthio-2- azetidine-noni-1-sulfonate.

1R »KBr cm -1: 3415, 3320, 1765, 1662, 1525, 1270, 1250, max 1048 PMR (DMSO-d 6, ppm): 0.88 (t, J« 7Hz, CH 3), 1.46 (m, -CH 2 - ), 2.76 (t, J * 7Hz, -CH 2 -) s 3.84 (s, CH 2), 5.14 (d, J * 6Hz, C 4 -H), 5.32 (dd, J * 6, 8Hz, C 1 H) , 6.90 (s,> rfH), 7.15 (s, NH 2), 9.37 (d, J * 8Hz, NH)

Example 73 Sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-n-butylthio-2-azetidinone-1-sulfonate 1) To solution with 0.40 g of (3R, 4S) -4-n-butylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone in 3 ml of DMF: a, a solution of 0.424 g of a complex of sulfur trioxide and DMF in 1.59 ml of DMF is added at -70 ° C. The reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.219 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.231 g of sodium (3R, 4S) -4-n-butylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) - 2-azetidinone-1-sulfonate.

1R vKBr cm_1i 3260, 1765, 1668, 1542, 1260, 1040

IHÄX

PMR (DHSO-d 6, ppm): 0.88 (m, CH 3>, 1.48 (m, -CH 2 -), 2.77 (m, -CH 2 -, 3.87 (s, CH 2), 4.36 (s, CH 2), 4.66 (dd , J «3, 8Hz, C3-H), 4.80 (d, J« 3Hz, C4-H), 7.38 (s, YH), 9.45 (d, J-8HZ, NH), 12.88 (s, NH) 2 ) To a solution of 0.18 g of sodium (3R, 4S) -4-n-butylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone -1-sulfonate in 15 ml of 30% ethanol, 0.052 g of sodium monomethylthiocarbamate, is added under ice-cooling, and the reaction is allowed to proceed at 0 [deg.] C. for 2 days, stirring for 1 hour at room temperature and purifying the reaction mixture in Example 72, 3 ) gives 0.056 g of sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-n-butylthio-2-azetidinone-1- sulfonate.

IR vKl3rcni- *; 3400, 3320, 1765, lbb2, 1530, 1270, 1 250,

1113 X

1048 1 H (DMSO-di>, ppm); 0.89 (m, CH 3), 1.24-1.7b (m, -CH 2 -), 2.68 (m, -CH 2 -), 3.85 (s, CH 3), 4.62 (dd, J = 3.8Hz, C, -H ), 4.81 (d, J = 3Hz (C 1 H -H), 6.66 (s, y "), 7.16 (s, NH 2), 9.32 (d, J = 8Hz, NH)

Example 74 Sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4 - ((n-propylthio) thiocarbonyl) thio-2-azetidinone- Isomer (A) of the 1-sulfonate and the corresponding (3R, 4R) -isomer (B)

To a solution of 0.420 g of (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4 - ((n-propylthio) thiocarbonyl) thio-2- azetidinone in 5 ml of DMF, a solution of 0.39 g of a complex of sulfur trioxide and DMF in 1.72 ml of DMF is added at -20 ° C. The mixture is stirred at 5 ° C for 2 days. Addition of 0.237 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.085 g of sodium (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4 - ( n-propylthio) -thiocarbonyl) thio-2-azetidinone-1-sulfonate isomer (A) and 0.119 g of the corresponding (3R, 4R) -isomer (B).

(A) IR ν max cm -1; 3240, 1778, 1663, 1539, 1278, 1039 max PMR (DMSO-d 6, ppm); 0.97 (t, J = 7Hz, CH 3), 1.68 (m, -CH 2 -) 3.36 (t, J = 7Hz, -CH 2 -), 3.93 (s, CH 3), 4.37 (s, C 1 CH 2 -), 4.96 (dd, J = 2.9Hz, C 3 -H), 5.88 (d, J = 2Hz, C4-H), 7.34 (5, γΗ), 9.58 (broad s, NH) 148 79528 (B) 1R v cm @ -1; 3500, 3260, 1773, 1668, 1540.

1270, 1045 PMR (DMSO-d 6, ppm): 0.96 (t, J®7Hz, CH-j), 1. 68 (m, CHCH 2 -), 3.36 (t, J = 7Hz, -CH 2 -), 3.b6 (s, CH 3), 4.35 (S, C 1 CH 2 -), 5.58 (dd, J = 5.9Hz, C 3 * H), 6.16 (d, J = 5Hz, C4-H), 7.18 (Β, γΗ), 9.38 (d, J = 9Hz, NH)

Example 75 Sodium (3R, 4S) -3- {2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4 - ((n-propylthio) thiocarbonyl} thio-2-azetidinone- 1-sulfonate and (3R, 4R) isomer

A suspension of 0.128 g of sodium (3R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4 - ((n-propylthio) thiocarbonyl) thio-2- azetidinone 1-sulfonate and 0.028 g of sodium monomethyldithiocarbamate in 3 ml of 30% methanol are stirred for 2 hours at room temperature. Purification of the reaction mixture according to Example 3 gives 0.023 g of sodium (3R, 4S) -3- (2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido) -4 - ((n-propylthio) thiocarbonyl). ) thio-2-azetidinone-1-sulfonate isomer (A) and 0.050 g of the corresponding (3R, 4R) -isomer (B).

(A) and 0.050 g of the corresponding (3R, 4R) -isomer (B).

(A) IR ν max Qi "1; 3310, 1775, 1661, 1613, 1520, 1272, 1250, 1048 PMR (DMSO-d 6, ppm); 0.97 (t, J-7Hz, CH 3), 1.68 (m, - CH2-), 3.34 (t, J-7Hz, -CH2_), 3.86 (s, CH3), 4.90 (dd, J <2.9Hz, C3-H), 5.87 (d, J = 2Hz, C4-H) , 6.60 (s, YH), 7.18 (broad s, NH), 9.48 (d, J-9Hz, NH) (B) IR ν max, 3310, 1774, 1661, 1612, 1520, 1272, 1250 max PMR ( DMSO-d 6, ppm) j 0.97 (t, J * 7Hz, CH 3), 1.68 (m, -CH 2 -), 3.34 (t, J * 7 Hz, -CH 2 -), 3.80 (s, CH 3), 5.52 (dd , J-5.9H *, C3-H), 6.13 (d, J <5Hz, C4-H), 6.48 (s, Y **), 7.18 (broad s, NH2>, 9.28 (d, J «9Hz) , HH) 149 79528

Example 76 Sodium (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) -hydroxybutanamido) -2-azetidinone 1-sulfonate 1) To a solution of 0.40 g of (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S ) -for-myloxybutanamido) -2-azetidinone in 3 ml of DMF, a solution of 0.432 g of a complex of sulfur trioxide and DMF in 1.61 ml of DMF is added at -20 ° C. The reaction is allowed to proceed at 4 ° C for 2 days. Addition of 0.224 g of pyridine to the reaction mixture and purification as described in Example 1 gives 0.282 g of sodium (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido)). -3- (S) -formyyliok-sibutan-amido) -2-azetidinone-1-sulfonate.

IR 'W01 "" 1' * 3460 '3270' 2105 '1775' 1710 '1665, 1515 # 1270/1248, 1180, 1045 PMH (DMSO-d6, ppra); 1.11 (t, J = 7Hz, CH3>, 1.23 (d, J = 6Hz, CH 3> 3.43 (q, J * 7Hz, -CH 2 -), 3.40-3.80 (m, -CH 2 -), 3.86-4.04 (m, -CH 2 -), 4.46 (dd, J = 2.8Hz, C3> H), 4.55 (dd, J <4.8Hz,?? H ”), 5.11 <d, J = 2Hz, C3 ~ H), 5.40 (», "? H"), 8.19 ( s, CHO), 9.10 (d, J-8Hz, NH), 9.36 (d, J-8Hz, NH) 2) To a solution of 0.10 g of sodium (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) -formyloxybutanamido) -2-azetidinone-1-sulfonate in 3 ml of water is added under ice-cooling 0.57 ml of 1N hydrochloric acid, followed by stirring for 30 minutes. Addition of 0.048 g of sodium bicarbonate to the reaction mixture and purification on an XAD-II column gives 0.036 g of sodium (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazine carboxylate). boksiamido) -3- (S) -hydroksibutanamido) -2-azetidinone-1-sulfonic sulfonate.

150 79528 IR νΚΒΓα »" 1 »3430-3300, 2115, 1775, 1705, 1670, 1518, max 1275, 1250, 1048 PMR (DMSO-d 6, pf * n); 1.08 (d, J» 6Hz, CH 3), 1.10 (t, J = 7Hz, CH 3), 3.42 (q, J * 7Hz, -CH 2 -), 3.56 (m, -CH 2 -), 3.94 (m, -CH 2 -), 4.00-4.24 (m, .), 4.42 (dd, J-2.8Hz, C3-H), 5.15 (d, J = 2Hz, C4-H), 5.18 (s, OH), 8.75 (d, J = 8Hz, NH). (d, J = 8Hz, NH)

Example 77 Sodium (3R, 4R) -4- (2-acetamidoethyl) thio-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -2-azetidinone-1 sulfonate 1) To a solution of 1.25 g of (3R) -4- (2-acetamidoethylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2 -azetidinone in 10 ml of DMP, a solution of 1.25 g of a complex of sulfur trioxide and DMF in 4.66 ml of DMF is added at -20 [deg.] C. The reaction is allowed to proceed at 4 [deg.] C. 2 Addition of 0.643 g of pyridine to the reaction mixture and purification as described in Example 1 gives 0.300 g of sodium (3R, 4S) -4- (2-acetamidoethylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2- methoxyiminoacetamido) -2-azetidinone-1-sulfonate isomer (A) and 0.367 g of the corresponding (3R, 4R) -isomer (B).

(A) IR cm -1 S 3250, 1767, 1660, 1540, 1260, 1038

llf «K

PMR (DMSO-d 6, pp «o); 1.85 (s, CH3), 2.86, 3.28 (each m, -CH2-), 3.90 (s, CH3), 4.37 (s, C1CH2-), 4.68 (dd, J <2.8Hz, C3-H), 4.86 (d, J «2Hz, C4-H), 7.41 (e, yH), 9.46 (d, J-8HZ, NH) (B) IR 3275, 1763, 1658, 1540, 1270, 1050,

IQaX

1038 PMR (DMSO-d 6, ppm); 1.81 (s, CH 2), 2.86, 3.24 (y, m, -CH 2 -), 3.88 (s, CH 3), 4.36 (s, C 1 CH 2 -), 5.18 (d, J «5Hz, C 4 -H), 5.36 ( dd, J> 5.8Hz, C3-H), 7.51 (s, YH), 9.50 (d, J-8Hz, NH) 151 79528 2) To a solution of 0.200 g of sodium (3R, 4S) -4- (3R, 4R) -isomer of (2-acetamidoethyl) thio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone-1-sulfonate (B) In 5 ml of water, 0.046 g of sodium monomethyldithiocarbamate are added under ice-cooling. After stirring for 2 hours at room temperature and purifying the reaction mixture as described in Example 3, 0.081 g of sodium (3R, 4R) -4- (2-acetamidoethyl) thio-3- (2- (2-aminothiazol-4-yl) -2-methoxy- imino-acetamido) -2-azetidinone-l-sulfonate.

IR vKBrcnf> 1; 3320, 1762, 1658, 1522, 1270, 1048 i & dx PMR (DMSO-d6, ppm); 1.80 (s, CH 3>, 2.82, 3.21 (each m, -CH 2 -), 3.84 (s, CH 3), 5.17 (d, J * 5H 2, C 4 -H), 5.33 (dd, J = 5.8 Hz, C 3 -H), 6.89 (s, 1H, NH), 7.18 (broad s, NH2), 7.88 (ra, NH), 9.40 (d, Js8Hz, NH)

Example 78 ____ Sodium (3R, 4S) -4 - ((2-acetamidoethyl) thio) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone-1- sulfonate

A mixture of 0.212 g of sodium (3R, 4S) -4- (2-acetamidoethyl) thio-3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-azetidinone 1-sulfonate and 0.049 g of sodium monomethyldithiocarbamate, are treated as described in Example 77, 2) to give 0.037 g of sodium (3R, 4S) -4- (2-acetamidoethyl) thio-3- (2- (2- <aminothiazole). -4-yl) -2-methoxyiminoacetamido) -2-azetidinone-1-sulfonate.

IR 3310, 1763, 1656, 1528, 1270, 1248, max 1043 PMR (DMSO-d 6, ppm) f 1.80 (a, CH 3), 2.86, 3.23 (each m, -CH 2 -), 3.87 (s, CH 3), 4.82 (d, J «2Hz, C4-H), 4.64 (dd, J« 2.8Hz, C3-H), 6.78 («, ^ Η), 9.40 (d, J-8Hz, NH) 152 7 9 5 2 8

Example 79 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio-2-azetidinone-1-sulfonate 1) To a solution of 0.552 g of (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexyl, lithio-2-azetidinone in 2 ml of DMF, a solution of 0.55 g of a complex of sulfur trioxide and DMF in 2.1 ml of DMF is added at -70 ° C. The reaction is allowed to proceed at 0 ° C for 30 hours. Addition of 0.5 ml of pyridine to the reaction mixture and purification as described in Example 6 gives 0.657 g of pyridinium- (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio- 2-azetidinone-l-sulfonate.

KBr 1 IR Vmaxcm; 1780, 1770, 1660, 1525, 1250, 1040 PMR (DMSO-d 6, ppm); 3.88 (s, OCH 3), 4.36 (s, -CH 2 -), 7.52 (s, yH), 9.44 (dd, J = 8 Hz, NH) 2) A mixture of 0.45 g of the pyridinium derivative obtained according to Example 79 1) and 0.104 g of sodium monomethyldithioannamate suspended in 50% methanol, stirred for 30 minutes at room temperature. Treatment as in Example 3 gives 0.113 g of sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio-2-azetidinone-1-sulfonate.

IR χίϊϊο ™ ”1 * 1765, 1660, 1620, 1525, 1250, 1045 Π & ΟΧ PMR (DMSO-d6, ppm); 3.84 (s, OCH 3), 4.24 (d, J = 5Hz, C 4 -H), 5.30 (dd, J * 5.8Hz, Cj-H), 6.92 (·, yH), 9.32 (d, J * 8Uz, NH)

Example 80 Sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio-2-azetidinone-1-sulfonate 4,153,79528 1) By treating ( 3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio-2-acetidinone as described in Example 79, 1) gives pyridinium (3R / 4S) ) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio-2-azetidinone-1-sulfonate.

IR vKörcnT *; 1765, 1670, 1540, 1265, 1045 max 1 PMR (DMSO-d 6, ppm): 3.90 (s, OCH 3), 4.36 is, -CH 2 -), 4.64 (dd, J = 2.8Hz, C 3 -H), 4.90 (d, J = 2Hz, C4-H), 7.36 (8, yH), 9.45 (d, J = 8Hz, NH) 2) By treating the pyridinium salt obtained according to Example 80, 1) according to Example 79, 2) Sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-cyclohexylthio-2-azetidinone-1-sulfonate is obtained.

IR ~ 11175, 1660, 1520, 1250, 1040

JuaX

1 'VIK (DMSO-d6, ppra); 3.95 (s, OCH 3), 4.89 (d, J = 2Hz, C 4 * H), 7.45 (β, γΗ), 9.50 (d, J = 8Hz, NH)

Example 81 Sodium 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-fluoro-2-azetidinone-1-sulfonate

To a solution of 0.54 g of 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-fluoro-2-azetidinone in 2 mL of DMF is added -70 ° C. in a solution of 0.70 g of a complex of sulfur trioxide and DMF in 2.6 ml of DMF. The reaction is allowed to proceed at 0 ° C for 2 days. Addition of 0.5 ml of pyridine to the reaction mixture and purification according to Example 1 gives 0.233 g of sodium 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-fluoro-2-azetidinone- 1-sulfonate.

KBr IR ν cm-1: 1780, 1675, 1540, 1270, 1040 max 154 79528

Example 82 Sodium (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-chloromethylacetamido) -4-methylthio-2-azetidinone-1- sulfonate

To a solution of 0.1 g of (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-chloromethylacetamido) -4-methylthio-2- oxoazetidine in 1 ml of DMF, a solution of 0.11 g of a complex of sulfur trioxide and DMF in 0.42 ml of DMF is added at -70 [deg.] C. The reaction is allowed to proceed at 0 [deg.] C. 3 days. Addition of 0.3 ml of pyridine to the reaction mixture and purification according to Example 1 gives 0.038 g of sodium (3R, 4R) -3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2 -kloorimetyyliasetamido) -4-methyl-thio-2-azetidinone-1-sulfonate.

KBr IR) cm-1; 1765, 1720, 1680, 1520, 1280, 1250, max 1050

Example 83 Sodium (3R, 4R) -4-t-butylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) -formyloxybutanamido) - 2-azetidinone-1-sulfonate

To a solution of 0.35 g of (3R, 4R) -4-t-butylthio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) -formyl -lixybutanamido) -2-azetidinone in 3 ml of DMF, a solution of 0.346 g of a complex of sulfur trioxide and DMF in 1.27 ml of DMF is added at -20 ° C. C. Add 0.18 g of pyridine to the reaction mixture and purify as in Example 1 to give 0.27 g of sodium (3R, 4R) -4-t-butylthio-3- (D-2- (4-ethyl- 2,3-dioxo-1-piperatsiinikarboksiamido) -3- (S) -for-myylioksibutanamido) -2-azetidinone-1-sulfonate.

155 79528 IRv? Cm -1; 3475, 3280, 1760, 1712, 1675, 1520, max 1275, 1250 PMR (DMSO-d 6, ppm); 0. bb (m.CH 2), 1.11 (t, J = 7Hz, CH 2), J, 20-1.66 (m, CH 3, -C'H 2 -), 2.74 (t, J-7H 2, "CH 2 ->, 3.42 (q, J = 7Hz, -CH 2 -) ), 3.60 (m, 3.94 (m, -CH- -), 4.67 (dd, J = 4.2 ru-CH-8HZ,,), 5.06-5.40 (m, C3-1l, C4-H, ), 8.16 (s, CHO), 9.11 (d, J-8Hz, NH), 9.37 (d, J * 8Hz, NH)

Example 84 Disodium (3S, 4S) -4-azido-3- (D-2- (2-oxo-3-sulfonate imidazolidin-1-ylcarboxamido) -2-phenylacetamido) -2-azetidinone-1- sulfonate

To a solution of 0.45 g of (3S, 4R) -4-azido-3- (D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido) -2-azetidinone in 4 ml. DMF, a solution of 0.55 g of a complex of sulfur trioxide and DMF in 2.1 ml of DMF is added at -20 ° C. The reaction is allowed to proceed at 5 ° C for 2 days. Addition of 0.29 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.12 g of disodium (3S, 4S) -4-azido-3- (D-2- (2-oxo-3-sulfonateimidazolidine). 1-yl-carboxamido) -2-phenylacetamido) -2-azetidinone-1-sulfonate.

TR g * ® * '»* 1» 3470, 3300, 1770, 1660, 1520, 1245, 1050 max} »\ 1R (DMSO-d 6, ppm): 3.30 (m, -CH 2 -), 3.70 (m, - CH2-), .5.12 (dd, J = 5.8Hz, C3-H), 5.35 (d, J = 5Hz, C4-H), 5.54 (d, J * 8Hz, "? H"), 7.20-7.60 (m, Aron ». H), 9.07 (d, J = 8Hz, NH), 9.24 (d, Jb8Hz, NH)

Example 85 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-i-propylthio-2-azetidinone-1-sulfonate 156 7 9 5 2 8 1) To a solution of 0.45 g of (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-i-propylthio-2 -azetidinone in 5 ml of DMF, a solution of 0.48 g of a complex of sulfur trioxide and DMF in 1.82 ml of DMF is added at -20 ° C. The reaction is allowed to proceed at 5 ° C for 2 days. Addition of 0.25 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.45 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- i-propylthio-2-azetidinone-1-sulfonate.

IR vKBrcm_1; 3260, 2950, 1768, 1668, 1542, 1250, max 1048 PMR (DMSO-d 6, ppm); 1.19.1.26 (min. D, J = 6Hz, ClI3), 3.3 (m, -CH <), 3.88 (s, CH3), 4.35 (s, C1CH2>), 5.24 (d, J-5Hz, C4 -H), 5.39 (dd, J * 5.9Hz, C3-H), 7.48 (s, y H), 9.43 (d, J = 9Hz, NH) 2) A solution of 0.275 g of sodium (3R, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-i-propylthio-2-azetidinone-1-sulfonate and 0.068 g of sodium monomethyldithiocarbamate in 5 ml 40% methanol, stirred for 2 hours at room temperature, after which purification according to Example 3 gives 0.077 g of sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) - 4-i-propylthio-2-azetidinone-1-sulfonate.

IR νΪΞαΓ1 * 3310, 1761, 1663, 1618, 1525, 1240, 1045

luaX

PMR (DMSO-d 6, ppm); 1.20, 1.26 (min. D, J = 6Hz, CH3), 3.3 (ia, ~ CHO, 3.84 (s, CH3), 5.22 (d, J = 5Hz, C4-H), 5.36 (dd, J = 5, 9Hz, C3-H), 6.88 (s, YH), 7.15 (broad s, NHj), 9.33 (d, J = 9Hz, NH) »T 79528

Example 86 Sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-i-propylthio-2-acetidinone-1-yl onate i

To a solution of 0.26 g of (3R, 4S) -2- (2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyiminoacetamido) -4-i-propylthio-2-azetidinone in 2 ml: DMF, a solution of 0.28 g of a complex of sulfur trioxide and DMF in 1.1 ml of DMF is added at -20 ° C. The reaction is allowed to proceed at 5 ° C for 2 days. Addition of 0.145 g of pyridine to the reaction mixture and purification according to Example 6 gives 82 mg of pyridinium- (3R, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4-i- propylthio-2-azetidinone-1-sulfonate. To a solution of this compound in 10 ml of 50% methanol is added sodium hydrogencarbonate to adjust the pH of the solution to 7. 0.08 g of sodium monomethyldithiocarbamate is added to the mixture, and the mixture is stirred for 1.5 hours at room temperature. Purification according to Example 3 gives sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-i-propylthio-2-azetidinone -1-sulfonate.

IR vKBrcm-1; 3320, 1763, 1670, 1618, 1523, 1242, 1045 max PMR (DMSO-d 6, ppm); 1.20, 1.28 (d., J-6Hz, CH3), 3.84 (s, CH3), 4.60 (dd, J-2.9ilz, C jH), 4.89 (d, J = 2Hz, C4-H), 6.67 (s, 1 H), 7.16 (broad s, NH 2), 9.34 (d, J-9Hz, NH)

Example 87 Sodium (3S, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-ethoxycarbonyl) methoxy-2-azetidinone 1-sulfonate 1

To a solution of 0.40 g of (3S, 4R) -3- (2- (2-chloroacetamidomethiazol-4-yl) -2-methoxyiminoacetamido) -4- (ethoxycarbonyl) methoxy-2- azetidinone in 3 ml of DMF, a solution of 0.41 g of a complex of sulfur trioxide and DMF 158 79528 in 1.53 ml of DMF is added at -20 ° C. The reaction is allowed to proceed at 5 ° C for 2 days. Addition of 0.212 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.35 g of sodium (3S, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (ethoxycarbonyl-methoxy-2-azetidinone-l-sulfonate.

IR vK®rCm ”^; 3400, 3250, 1772, 1740, 1670, 1540, max 1262, 1042 PMR (DMSO-d 6, ppm) j 1.20 (t, J = 7Hz, CH 3), J.87 (s, CH 3), 4.15 (q, J = 7Hz, -CH 2 -), 4.33 (s, -CH 2 -), 4.45 (ABq, J = 24.39Hz, -CH 2 -), 5.18 (dd, J = 5.9Hz, C 1 H), 5.38 ( d, J = 5HZ, C4-H), 7.63 (8, Y ^), 9.4 3 (d, J = 91lz, NH), 12.80 (broad S, NH) 2) To a solution of 0.20 g of the preceding paragraph 1) of the confirmed sulfonate derivative in 7 ml of water, 0.052 g of sodium monomethyldithiocarbamate is added under ice-cooling, and the mixture is stirred for 50 minutes at room temperature. Purification by XAD-II column chromatography under ice-cooling gives 0.053 g of sodium (3S, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-4-ethoxycarbonyl) methoxy -2-azetidinone-1-sulfonate.

IR vKBrcm ”*; 3400, 3320, 1772, 1735, 1665, 1522, max 1270, 1238, 1128, 1045 PMR (DMSO-d 6, ppm); 1.22 (t, J = 7Hz, CHj), J.82 (s, CH3> (4.14 (q, J * 7Hz, -C112-), 4.4b (s.-CHj-), 5.15 (dd, J = 5 , 8Hz, C3-H), 5.36 (d, J1-5Hz, C4-H), 6.97 (s, N1-11), 7.10 (s, N12), 9.29 (d, J = 8Hz, NH)

Example 88 Sodium (3S, 4S) -4-azido-3 - () - 2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) -hydroxybutanamido) -2-azetidinone 1-sulfonate 159 79528 1) To a solution of 0.40 g of (3S, 4R) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3 - (S) -formyloxybutanamido) -2-azetidinone in 3 ml of DMF, a solution of 0.433 g of a complex of sulfur trioxide and DMF in 1.62 ml of DMF is added at -20 ° C. . The mixture is allowed to stand at 0 ° C for 2 days. Addition of 0.224 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.202 g of sodium (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3 - (S) -formyloxybutanamido) -2-azetidinone-1-sulfonate.

IR 3450, 1770, 1708, 1670, 1515, 1275,

UlflX

1185, 1048 I »MR (DMSO-d 6, ppm) ί 1.10 (t, J> 71Iz, CII3>, J. 24 (> 1, J-6IIZ, CH 2), 3.41 (q, J = 7Hz, -CH ., -), J. 56 (m, -CH, -), A —PH- ^ 3.93 (m, -CH--), 4.64 (dd, J-3.9Hz,,), ^ —PH · * 5.08 (dd, J = 5.8Hz, C3-H), 5.37 (m,,), 5.43 (d, J <5Hz, C4-H), 8.17 (s, CHO), 9.10 (d, J * 8HZ, NH), 9.36 (d, J = 9 Hz, NH) 2) To a solution of 0.15 g of the sulfonate derivative obtained in 1) in 3 ml of water is added 0.86 ml of N HCl under ice-cooling. The mixture, to which 0.072 g of sodium hydrogen carbonate has been added, is stirred for 1 1/2 hours at room temperature.

Purification by XAD-II column chromatography afforded 84 mg of sodium (3S, 4S) -4-azido-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) -hydroksibutanamido) -2-azetidinone-1-sulfonate.

IR vKBrcm "^; 3440, 3300, 1772, 1705, 1670, 1510,

IBdX

1270, 1192 PMR (DMSO-d6, ppro); 1.10 (t, J = 7Hz, CH3), 1.14 (d, J * 6Hz, CH3), 3.42 (q, J = 7Hz, -CH--), 3.56 (m, -CH--), 3.92 (m , -CH 2 -), 4.07 (m, V), 5.13 (dd, J (5.8Hz, C 3 -H), 5.40 (d, J = 5Hz, C 4-1), 8.78 (d, J = 8Hz, NH ), 9.24 (d, J * 8Hz, NH) ι «° 79528

Example 89 Using 0.40 g of (3S, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (ethoxycarbamyl) methoxy-2-acetidinone and applying the procedure of Example 88 to give 0.07 g of sodium (3S, 4S) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (ethoxycarbonyl) methoxy-2-azetidinone-1-sulfonate.

1R \> KBrcm ”*? 3420, 1772, 1738, 1068, 1640, 1270, max 1230, 1035 PMK (DMSO-d 6, ppio); 1.21 (t, J = 7 Hz, CH 2). 3.90 (s, CH 2), 4.13 (q, J <7 Hz, -CH 2 -), 4.36 (s,), 4.49 (s, -CH 2 -), 4.66 (dd, J = 2.8 Hz, C 3 - H), 5.23 (d, J * 2Hz, C4-H), 7.42 (8, ^ “), 9.38 (d, J * 8Hz, NH)

Example 90 Sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-methoxy-4-methylthio-2-oxoazetidine-1-sulfonate 1) To solution with 0.262 g of (3S, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -3-methoxy-4-methylthio-2-oxoazetidine in 3 ml DMF, a solution of 0.287 g of a complex of sulfur trioxide and DMF in 1.07 ml of DMF is added at -70 ° C. The reaction mixture is allowed to stand at 0 ° C for 2 days. Addition of pyridine to the reaction mixture and purification according to Example 1 gives 0.254 g of sodium (3S, 4R) -3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -3- methoxy-4-methylthio-2-oxoazetidine-1-sulfonate.

KBr IR) cm -1; 3230, 1770, 1675, 1540, 1260, 1045 max 2) To a solution of 0.158 g of the sulfonate derivative obtained in 1) above in 2 ml of water is added 161,79528 of ice-cooled 43 mg of sodium monomethyldithiocarbamate, and the mixture is stirred for one hour. followed by purification according to Example 3 to give 78 mg of sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-methoxy-4-methylthio -2-oksoatse-via amination-l-sulfonate.

KBr IR v! cm-1; 1773, 1670, 1620, 1525, 1250, 1050 max

Example 91 Sodium (3S, 4S) -4-azido-3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -4-pentynamido) -2-oxoacetidine-1-sulfonate

To a solution of 0.40 g of (3S, 4S) -4-azido-3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -4-pentynylamido) -2-oxoazetidine in 3 ml DMF, a solution is added at -70 ° C if there is a complex of 0.47 g of sulfur trioxide and DMF in 1.76 ml of DMF. The mixture is allowed to stand at 0 ° C for 2 days.

Addition of 0.244 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.297 g of sodium (3S, 4S) -4-azido-3- (2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -4- pentyyniamido) -2-oksoatseti-pyrrolidine-1-sulfonate.

IR vKBrcm -1; 3470, 3270, 2110, 1775, 1708, 1670, 1510, max 1280-1240, 1048 PMR (DMSO-d 6, ppro): 1.10 (t, J «7Hz, CH 3), 2.70 (m, - CH 2 '), 2.84 (m, HC 2), 3.41 (q, J-7H *, - CH 2 -), 3.57 (m, -CH 2 -), 3.92 (m, -CH 2 -), 4.53 (m, -CH 2 -), ), 5.09, 5.13 (each dd, J-5, 8Hz, C3-H), 5.44, 5.47 (each dd, J-5Hz, C4 «H), 8.99, 9.02 (each d, J« 8Bz, NH), 9.42 (d, J-8Hz, NH) 162 7 9 5 2 8

Example 92 Sodium (3R, 4R) -4- (2-acetamidoethylthio) -3-O-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2- oxoacetidine-1-sulfonate and the (3R, 4S) -isomer

To a solution of 1.0 g of (3R) -4- (2-acetamidoethyl) thio-3- (D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido) -2- oxoazetidine in 5 ml of DMF, a solution of 0.90 g of a complex of sulfur trioxide and DMF in 3.4 ml of DMF is added at -70 ° C. The mixture is allowed to stand at 0 ° C for 2 days.

Addition of 0.470 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.402 g of sodium (3R, 4R) -4- (2-acetamidoethylthio) -3- (D-2- (4-ethyl-2,3-dioxo-1- piperazinecarboxamido) -2-phenylacetamido) -2-oxoazetidine-1-sulfonate isomer A and 0.132 g of the corresponding (3R, 4S) -isomer B.

(A) IR v * ® ** »” 1: 3280, 1768, 1712, 1670, 1505, 1272,

ITlaX

1243, 1042 PMR (DMSO-d 6): 1.08 (t, J-7Hz, CH 3), 1.78 (s, CH 2), .3.40 (q, J «7H *, - CH 2 -), 5.05 (d, J * 5Hz , C4-H), 5.26 (dd, J * 5.8Hz, C3-H), 5.58 (d ^ «8Hz," 9H "), 9.27 {d, J * 8Hz, NH>, 9.79 <d, J * 8Hz, NH) (ppm) (B) IR ν max Jfn »3290, 1765, 1710, 1670, 1503, 1250,

XQaX

1185, 1043 PMR (DMSO-d 6, ppm): 1.09 (t, J 7 Hz, CH 3), 1.78 (s, CH 3), 3.40 (q, J 7 Hz, -CH 2 -), 4.57 (dd, J-3) , 8Hz (Cj-H), 4.70 (d, J «3Hz, C4-H), 5.43 (d, J« 8Hz, "? H '), 9.32 (d, J-8Hz, NH), 9.77 (d, J «8Hz, NH)

Example 93 (3S, 4S) -4-Azido-3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine-1-sulfonic acid 163 79528 1) To a solution of 0 .60 g of (3S, 4R) -4-azido-3- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -2-oxoazetidine in 4 ml of DMF are added at -20 ° In C, a solution of 0.814 g of a complex of sulfur trioxide and DMF in 3.04 ml of DMF. The mixture is allowed to stand at 0 ° C for 2 days.

Addition of 0.422 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.571 g of sodium (3S, 4S) -4-azido-3- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -2- oxoazetidine-l-sulfonate.

IR νκBcm-1} 3480, 3280, 2112, 1775, 1660, 1540, 1280, max 1242, 1053 PMR (DMSO-d 6, ppm); 3.90 (s, CH 3), 5.21 (dd, J = 2.8 Hz, C 3 -H), 5.45 (d, J (5 Hz, C 4 -H), 7.42 (8, 2), 8.50 (e, CHO), 9.50 (d, J = 8 Hz, NH), 12.55 (6, NH) 2) To 0.25 g of the sulfonate derivative obtained in 1 is added 1.7 ml of N-HCl and 2 ml of methanol and the mixture is stirred for 2.5 hours. at room temperature.

0.144 g of sodium hydrogen carbonate are added to the mixture under ice-cooling, whereupon crystals separate which are collected by filtration to give 0.074 g of (3S, 4S) -4-azido-3- (2- (2-aminothiazol-4-yl) -2-methoxy -iminoasetamido) -2-oksoatse-via amination-l-sulfonic acid.

IR vTOrcm_1; 3395, 2125, 1795, 1660, 1528, 1275, 1055 max PMR (DMSO-d 6, ppfn); 3.95 (s, CH 2), 5.18 (dd, J * 5.8Hz, C 3 "H), 5.51 (d, J-5Hz, C 4 -H), 7.01 (β, Π, 9.62 (d, J" 8Hz) , NH)

Example 94 Sodium (4- (2-acetamidoethyl) thio-3- (2- (2-aminothiazol-4-yl) -2 - ((2-oxo-3- (thiophene-3-aldoimino) imidate) solid-1-yl) -carboxamido) acetamido) -2-oxoacetidine-1-sulfonate mixture of cis and trans isomers 1

To a solution of 0.774 g of 4- (2-acetamidoethyl) -thio-3- (2- (2-chloroacetamidothiazol-4-yl) -2 - ((2-oxo-3- (thio- 164 7 9 5 2 8 Phen-3-aminoimino) imidazolidin-1-yl) -carboxamido) -2-acetamido) -2-oxoazetidine in 7 ml of DMF is added at -20 ° C a solution of 0.54 g a complex of sulfur trioxide and DMF in 2.03 ml of DMF. The mixture is allowed to stand at 5 ° C for 2 days. 0.280 g of pyridine is added to the reaction mixture, followed by purification according to Example 1 to give 0.107 g of sodium (4- (2-acetamidoethyl) thio-3- (2- (2-chloroacetamidothiazol-4-yl) -2 - ((2 -oxo-3- (thiophene-3-aldoimino) imidazolidin-1-yl) carboxamido) acetamido) -2-oxoazetidine-1-sulfonate is a mixture of cis and trans isomers.

IR vKBrcni ~ *; 3300, 1761, 1722, 1670, 1523, 1268, 1228, max 1045 PMR (DMSO-d 6, ppm): 1.80 (δ, λK), 4.34 (β, ΟΙΟΗ ^ -), 5.10 (dd, J * 5.8Hz) , C, -H), 5.51, 5.64 (min. D, J »8Hz, _9H"), 7.19.

7.25 (joteh. S, yH), 7.4-7.65 (m, Aron, H), 7.85, 7.89 (every s, -CH-), 8.92, 9.02 (each d, J-8Hz, NH) 2) To the solution, containing 80 mg of the sulfonate derivative obtained in 1) above in 4 ml of water, 14 mg of sodium monomethyldithiocarbamate are added under ice-cooling and stirred for 3.5 hours at room temperature, followed by purification as in Example 3 to give 24.3 g of sodium - (4- (2-acetamidoethyl) thio-3- (2- (2-aminothiazol-4-yl) -2 - ((2-oxo-3- (thiophene-3-aldoimino) imidazolidine) -yl) carboxamido) acetamido) -2-oxoazetidine-1-sulfonate is a mixture of cis and trans isomers.

IR vJiicnf1; 3300, 1760, 1720, 1660, 1510, 1268,

IuaX

1225, 1043 PMR (DMSO-d 6, ppm) t 1.79, 1.81 (min. S, CU3), 3.83 (broad, α-CH2-), 4.62 (dd, J <2.8Hz, C3-H), 4.83 ( d, J = 2Hz, C4-H), 5.12 (dd, J <5.8Hz, C3-H), 5.30 (d, j * 5Hz, C4-H), 5.40, 5.43 (min. d, J-8Hz) , “? H”), 6.54, 6.62 (y. S, Y11), 7.4-7.65 (ra, aroin. H), 7.86, 7JB9 (y. S, «CH-), 8.84, 8.88 (y. D, J (8Hz, NH) 165 79528

Example 95 (3R, 4R) -4- (2-Acetamidoethyl) -thio-3- (2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido) - 2-oxoazetidine-1-sulfonic acid 1) To a solution of 0.43 (3R, 4R) -4- (2-acetamidoethyl) thio-3- (2- (2-chloroacetamidothiazol-4-yl) -2 - (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino) acetamido) -2-oxoazetidine in 2 ml of DMF, a solution of 0.55 g of sulfur trioxide and DMF is added at -20 ° C: n complex in 2 ml of DMF. The mixture is allowed to stand at 0 ° C for 3 days.

0.5 g of pyridine is added to the reaction mixture. The mixture is concentrated under reduced pressure, and the residue is dissolved in 4 ml of methanol to which 0.6 g of tetra-n-butylammonium fluoride has been added, followed by concentration. The residue is purified by silica gel column chromatography to give 0.63 g of tetra-n-butylammonium- (3R, 4R) -4- (2-acetamido-ethyl) thio-3- (2- (2-chloroacetamidothiazole-4-). yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonylethoxyimino) acetamido) -2-oxoazetidine-1-sulfonate.

2) To a solution of 0.62 g of the chloroacetyl derivative obtained in 1) above in 2 ml of DMF is added a solution of 0.096 g of sodium monomethyldithiocarbamate in 0.3 ml of water, followed by stirring for 15 minutes at 25 ° C: in.

0.6 g of tetra-n-butylammonium fluoride is added to the mixture, and the mixture is stirred for 30 minutes at 25 ° C.

The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in 20 ml of ethyl acetate, followed by extraction with water (5 ml x 5). To the combined extract is added 8 ml of Dowex 50W H + type ion exchange resin and stirred for 15 minutes.

166 79528

The reaction mixture is filtered and the filtrate is purified by XAD-II column chromatography to give 0.044 g of (3R, 4R) -4- (2-acetamidoethyl) thio-3- (2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxy-imino) acetamido) -2-oxoazetidine-1-sulfonic acid.

IR \ »KBrcm_1; 1765, 1630, 1540, 1260, 1040 PMR (DMSO-d 6, ppm); 1.50 (s.CH3), 1.80 (s, COCH3), 2. «4 (t, J * 6Hz, -SCH2-), 3.22 (m, -CH2-), 5.21 (d, J = 4Hz, C4-H ), 5.34 (dd, J »4.8H2, C3-H), 7.10 (5, ^), 7.80-8.00 (m, NH), 9.38 (d, J * 8Hz, NH)

Example 96 (3R ', 4R) -4-Methylthio-3- (2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido) -2-oxoacetidine -1-sulfonic acid 1) To a solution of 0.58 g of (3R, 4R) -4-methylthio-3- (2- (2-trimethylaminothiazol-4-yl) -2- (1-methyl-1- (2 (tri-methylsilylethoxycarbonyl) -ethoxyimino) -acetamido) -2-oxoazetidine in 2 ml of DMF, 0.6 g of tetra-n-butylammonium fluoride are added and the mixture is stirred for 30 minutes and then evaporated to dryness under reduced pressure. The residue is dissolved in 2 parts of OMF and 0.55 g of a complex of sulfur trioxide and DMF in 2 ml of DMF is added to the solution at -70 ° C, after which the reaction mixture is allowed to stand at 0 ° C for 2 days.

0.5 g of pyridine is added to the reaction mixture, and the mixture is concentrated under reduced pressure. The residue is dissolved in 50% methanol to which 10 ml of Dowex 50W H + type ion exchange resin have been added, followed by stirring for 30 minutes.

The mixture is filtered, and sodium hydrogencarbonate is added to the filtrate to adjust the pH of the solution to 6.5.

79528

Purify by XAD-II column chromatography to give 0.24 g of disodium (3R, 4R) -4-methylthio-3- (2- (2-tritylaminothiazol-4-yl) -2- (1-carboxylate). l-methyl-ethoxyimino) acetamido) -2-oxoazetidine-1-sulfonate.

1R 1760, 1670, 1590, 1525, 1270, 1050 PMH (DMSO-d 6, ppm); 1.38 (s, CH3), 1.45 (s, CH3), 2.14 (s ^ CH3), 5.03 (d, J = 4Hz, C4-H), 5.30 (dd, J = 4.8Hz, C3-H), 6.70 (s, ^) * 7.20-7.45 (m * arom H), 8.70 (luveii s, NH), 11.04 (d, J = 8Hz, NH) 2) To a solution of 0.19 g according to 1) above of the resulting sulfonate derivative in 3 ml of 50% methanol, 0.5 ml of 1 N HCl is added and the mixture is stirred for 3 hours at 25 ° C.

The methanol is evaporated under reduced pressure to give triphenylcarbinol which is removed by filtration. The filtrate is purified by XAD-II column chromatography to give 0.09 g of (3R, 4R) -4-methylthio-3- (2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxy). -imino) acetamido) -2-oxoazetidine-1-sulfonic acid.

IR λmax01 "1 '* 1760» 1630' 1S4 ° * 126 ° '1040 PMH (D 2 O * external standard, ppm); 1.64 (s, CH 2), 2.35 (s, SCH 3), 5.50 (d, J «5Hz , C4-H), 5.60 (d, J = 5Hz, C3-H), 7.30 (ε, γΗ).

Example 97 Cis- and trans-sodium 3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2-formamidoethyl) thio-2-oxoazetidine-1-sulfonate mixture of isomers 1

To a solution of 0.710 g of 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2-formamidoethyl) thio-2-oxoazetidine in 3 mL of DMF , a solution of 0.77 g of a complex of sulfur dioxide and DMF in 3 ml of DMF is added at -20 ° C. The mixture is allowed to stand at 4 ° C for 2 days.

ui 79528

Addition of 0.40 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.332 g of sodium 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2-formamidoethyl) thio- A mixture of cis and trans isomers of 2-oxoazetidine-1-sulfonate.

IR vKBrcm_1; 3450, 3250, 1761, 1660, 1535, 1250, 1042 max.

PMR (DMSO-d 6, ppm); 2.8-3.1 (m, -CH2-), 3.5-3.8 (m, -CH2-J * 3.90 (s, CH3), 4.38 (s, C1CH2-), 4.75 (dd, J = 2.8 Hz.Cj- H trans), 5.02 (d, J = 2Hz, C ^ -H trans), 5.34 (dd, J = 5.8Hz, C3-H cis), 7.42,7.52 (sq. ^ "), 9.46 (d , J <8Hz, NH), 8.74 (s, CHO> 2) A solution of 0.273 g of the sulfonate derivative obtained in 1) above and 0.064 g of sodium monomethyldithiocarbamate in 2 ml of water is stirred for 1 hour at room temperature, then Purified according to Example 3 to give 0.110 g of sodium 3-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2-formamidoethyl) thio-2-oxoazetidine-1-sulfonate cis and a mixture of trans isomers.

IR N 2 ^ cnT1; 3430, 3310, 1766, 1660, 1522, 1240, 1052

luaX

pMH (DMSO-d 6, ppm); 2.7-3.0 (m, -CH2-), 3.B6 (s, CH3) 5.00 (d, J = 2Hz, C2-H trans), 5.24 (d, J = 2Hz, C3-H trans), 5.25 ( d, J * 5Hz, C ^ -H cis), 5.28 (dd, J <5.8Hz, C3 ~ H cis), 6.78, 6.96 (jiain. s, γΗ), 8.69, 8.70 (jckain. s, CHO) , 9.38 (d, J ~ 8Hz, NH) ·

Example 98 Sodium (3R, 4R) -4- (Z-2-acetamidovinyl) thio-3- (2- (2-chloroacetamido) -2-methoxyiminoacetamido) -2-oxoacetidine-1-sulfonate

To a solution of 0.30 g of (3R, 4R) -4- (Z-2-acetamidovinyl) -thio-3- (2- (2-chloroacetamido) -2-methoxyiminoacetamido) -2-oxoazetidine 3 in ml of DMF, a solution of 0.299 g of a complex of sulfur trioxide and DMF in 1.17 ml of DMF is added at -20 ° C. The mixture is allowed to stand at 0 ° C for 2 days.

169 79528

Addition of 0.154 g of pyridine to the reaction mixture and purification according to Example 1 gives 0.071 g of sodium (3R, 4R) -4- (Z-2-acetamidovinyl) thio-3- (2- (2-chloroacetamido) -2- methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate.

IRV ^ cn "1, 3470, 3280, 1768, 1660, 1620, 1545, 1260, max 1050 PMR (DMSO-d 6, ppm): 1.98 (s, CH 3>, 3.88 (ε, ΟΗ ^), 4.36 (s, -CH2-), 5.11 (d, j = 5Hz, C4-H), 5.32 (d, J <8Hz, |> =), 5.36 (dd, J = 5.8Hz, C3-H), 6.97 (dd , J * = 8.10Hz, <[J], 7.48 (s, ^ H), 9.42 (d, J * 8Hz, NH), 9.49 (d, J * 10Hz, NH).

Example 99 (3R, 4R) -3- (2- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido) -4- (2-amino-ethyl) -thio-2-oxo-azetidine-1-sulfonate 1) with 1.4 g of 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2- (p-nitrobenzyloxycarboxamidoethyl) thio) -2-oxoazetidine per ml of DMF, a solution of 1.37 g of a complex of sulfur trioxide and DMF in 4.13 ml of DMF is added at -20 ° C. The mixture is allowed to stand at 4 ° C for 2 days.

Addition of 0.76 g of pyridine to the reaction mixture and purification according to Example 1 gives 1.1 g of sodium 3- (2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido) -4- (2- (p-nitrobenzyloxycarboxamido) -ethyl) thio) -2-oxoazetidine-1-sulfonate a mixture of cis and trans isomers.

KBr IR> J cm -1; 3250, 1792, 1762, 1700, 1685, 1656 max 1510, 1344, 1250, 1038 170 79528 2) Dissolve 0.688 g of the sulfonate derivative obtained in 1) above and 0.142 g of sodium monomethyldithiocarbamate. to a mixture of 4.5 ml of DMF and 0.3 ml of H 2 O and the mixture is stirred for 5 hours at room temperature.

i

The solvent is distilled off and the residue is purified as in Example 3 to give 0.324 g of sodium - (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4- ( 2- (p-nitrobenzyloxy carboxamido) ethyl) thio-2-oxoazetidine-1-sulfonate.

IR VKBrcm_1; 3320, 1765. 1708, 1670, 1608. 1517, 1347, max 1250. 1048 PMH (DMSO-d 6, ppm); 2.7-3.0 (m, -CH 2 -), 3.1-3. S (m, -CH 2 -), 3.84 (s, CH 3), 5.18 (s, -CH 2 -), 5.24 (d, <= 5Hz, C 4-11), 5.30 (dd, J = 5.8Hz, C 3 -H ), 6.89 (s, ^ iM) »7-6 (>, 8.20 (.i <'price.d, *> = 9Hz, arom II), 9.39 (d, j = 8Hz, NH).

3) Dissolve 0.257 g of the sulfonate derivative obtained in 2) above in a mixture of 6 ml of THF and 4 ml of a buffer solution (pH * 7) to which 0.250 g of 10% palladium on carbon has been added, followed by stirring for 30 minutes under a stream of hydrogen. .

The resulting solid is removed by filtration and the filtrate is evaporated to remove THF, followed by purification by column chromatography on XAD-II to give 0.10 g of (3R, 4R) -3- (2- (2-aminothiazol-4-yl) - 2-methoxy-iminoasetami-do) -4- (2-aminoethyl) thio-2-oxoazetidine-1-sulfonate.

IR ^ ficra "1; 3310, 3200, 1769, 1660, 1610, 1525, 1240,

IDdX

104Q

PMR (DMSO-dg.ppm); 2.8-3.3 (m, -CH 2 -), 3.85 (s, CH 3), 5.23 (d, J = 5Hz, C 4 -H), 5.32 (dd, J * 5.8Hz, C 3 -H), 6.86 (s, yH), 7.13 (broad s.NHj), 7.76 (broad s, NH 2>, 9.40 (d, J = 8Hz, NH).

Example 100 Sodium (3R, 4R) -4- (2-acetamidoethyl) thio-3- (2- (2-formamidothiazol-4-yl) -2-tetrazol-5-yl) methoxy] 171 79528 iminoacetamido) -2 -oksoatsetidiini-1-sulfonate

To a solution of 0.144 g of (3R, 4R) -4- (2-acetamidoethyl) -thio-3- (2- (2-formamidothiazol-4-yl) -2- (1-sodium tetrazol-5-yl) methoxy- iminoacetamido) -2-oxoazetidine in 1.5 ml of DMF, a solution of 0.285 g of a complex of sulfur trioxide and DMF in 0.86 ml of DMF is added at -20 ° C. The mixture is allowed to stand at 0 ° C for 3 days.

Addition of 0.12 ml of pyridine to the reaction mixture and purification according to Example 1 gives 0.120 g of sodium (3R, 4R) -4- (2-acetamidoethyl) thio-3- (2- (2-formamidothiazol-4-yl) ) -2- (tetrazol-5-yl) -methoxyiminoacetamido) -2-oxoazetidine-1-sulfonate.

IR 1) KBrcm -1? 1765, 1655, 1545, 1270, 1050 max PMK (DMSO-d 6, ppm); 1.83 (s, CH 2), 5.18 (d, J = 5Hz, C 4 * H), 5.30 (s, -CH 2 -, 5.36 (dd, J * 5.8Hz, C 3 -H), 7.46 (8, 4), 8.1-8.35 (m, NH), 8.52 (s, CHO), 9.98 (d, J = 8Hz) , NH).

Example 101 Tetra-n-butylammonium (3S, 4S) -4-acetamido-3- (2-trimethylsilylethoxycarboxamido) -2-oxoacetidine-1-sulfonate 1) To a solution of 1.085 g of (3S, 4R) -4- azido-3- (2-trimethylsilylethoxycarboxamido) -2-oxoazetidine in 3 ml of DMF, a solution of a complex of 1.225 g of sulfur trioxide and DMF in 4.8 ml of DMF is added at -70 ° C with stirring, and the mixture is allowed to stand for 60 hours at 0 ° C.

0.632 g of pyridine are added, after which the solvent is removed by distillation under reduced pressure, and the residue is dissolved in a solution of 2.220 g of tetra-n-butylammonium chloride in 10 ml of dichloromethane.

172 79528

The resulting mixture is chromatographed on a silica gel column (eluting with a 4: 4: 1 mixture of ethyl acetate, chloroform and methanol) to give 2,300 g of tetra-n-butylammonium (3S, 4R) -4-azido-3- (2-trimethylsilylethoxycarboxamido). 2-oxoazetidine-1-sulfonate.

lR0KBrcm_1; 2110, 1780, 1720, 1670, 1250 max PMR (CDCl 3); 0.03 (s, si (CH 2) 3> / 0.90 (t, J-6Hz, CH 2), 2.10-2.80 (m, -CH 2 -), 3.00-3.30 (ro, -CHO-), 4.20 (t, J = 8 Hz, -CH 2 O-), 4.90 (d, J-4H 2, C 4 -H), 5.20 (dd, J = 4, bliz, C jH), 6.20 (d, J = 8Hz, MH) 2) , containing 1.185 g of the sulfonate derivative obtained in 1) above, 0.500 g of 10% palladium on carbon, 0.500 g of acetic anhydride and 10 ml of ethyl acetate are stirred for 2 hours under a stream of hydrogen at room temperature.

t

The reaction mixture is filtered and the filtrate is chromatographed on a silica gel column (eluting with a 4: 4: 1 mixture of ethyl acetate, chloroform and methanol) to give 0.432 g of tetra-n-butylammonium (3S, 4S) -4-acetamido-3- (2-trimethylsilyl-ethoxycarboxamido). -2-oxoazetidine-1-sulfonate.

IR Λπΐ "1! 1780, 1720, 1670, 1530, 1250 nex PMR (in CDCl3, pp«) j 0.03 <s, Si (CH3) 3), 0.90 (t, J = 6Hz, CH3), 2.00 (s, COCH3), 2.10-2.80 (m, -CH2-), 3.00-3.30 (m, -CH2-), 4.20 (t, J = 8Hz, -CH2O-), 4.70 (m, C4-H), 5.10 (m , C3-H), 6.00 (d, J = 8Hz, NH), 6.80 (d, J = 8Hz)

Example 102 Sodium (3S, 4S) -4-azido-3- (2- (2-tritylaminothiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino) acetamido) -2-oxoazetidine-1-sulfonate

To a solution of 0.80 g of (3S, 4R) -4-azido-3- (2- (2-tritylaminothiazol-4-yl) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxy -imino) acetamido) -2-oxoazetidine in 4 ml of DMF, at -20 ° C, 173 79528 0.505 g of a complex of sulfur trioxide and DMF in 1.98 ml of DMF are added and the reaction is allowed to proceed. At 2 ° C for 2 days. 0.26 g of pyridine and diethyl ether are added to the reaction mixture, followed by work-up as in Example 1 to give 0.673 g of sodium (3S, 4S) -4-azido-3- (2- (2-tritylaminothiazol-4-yl) ) -2- (1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyimino) -set-mido) -2-oxoazetidine-l-sulfonate.

IR 3380, 2115, 1778, 1728, 1676, 1512, 1282, max '1245, 1050 PMK (DMSO-d 6, ppm); 0.05 (s, CH 3), 0.95 (t, J = BHz, -CH, -), 4.13 (t, J = 8Hz, -CH 2 -), 5.14 (dd, j = 5.8Hz, C 3 -H) , 5.44 (d, J = SHz, C4-H), 6.70 (s, γ ”), 7.15-7.53 (m, arom .H), 8.73 (s, NH), 9.08 (d, J« 8Hz, NH)

Example 103

250 mg of (3R, 4R) -4- (2-acetamidoethyl) thio-3- (2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido) are added. 2-Oxoazetidine-1-sulfonic acid in a sterile 12 ml ampoule, which is then sealed at 6.66 kPa.

Example 104

500 mg of (3R, 4R) -4-methylthio-3- (2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido) -2-oxoazetidine-1 sulfonic acid in a 17 ml ampoule, which is then sealed.

Example 105

250 g of "Cefotiam" and 250 g of (3R, 4R) -4-methylthio-3- (2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxy) are mixed under aseptic conditions. imino) -acetamido) -2-oxoazetidine-1-sulfonic acid and the mixture is placed in sterile 12 ml ampoules at a rate of 250 mg per 174,79528 ampoules. The ampoules are then sealed at a pressure of 6.66 kPa.

Example 106

Place 250 mg of sodium (3R, 4R) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine-1-sulfonate in a sterile 12 ml ampoule. .

Example 107

Place 500 mg of sodium (3R, 4S) -3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-phenylthio-2-oxoazetidine-1-sulfonate in a 17 ml ampoule, which is then closed.

i i

Claims (5)

175 79528 A process for preparing a pharmaceutically active 1-sulfo-2-oxoazetidine compound represented by the following formula “-γΎ4 1 (I) J-N-SO3H O wherein X is hydrogen or methoxy; R 1 is (1) amino, (2) acylated amino, wherein the acyl group is (A) a group of the formula R 9 -CO- wherein R 6 is a 5- or 6-membered heterocyclic group containing one or two nitrogen atoms and optionally one oxygen atom, such as isoxazolyl, piperazinyl, imidazolinyl, etc., and which may be substituted by (a) lower alkyl or (b) phenyl optionally substituted by halogen; (B) a group of the formula R7-NH-CH-CO- 'I Rg 176 79528 wherein R7 is (i) a group of the formula Rg-CO-, wherein Rg is 5- or 6-membered, 2 .. .4 a nitrogen atom-containing heterocyclic group such as pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolinyl, imidazolidinyl, tetrazolyl, triazinyl, etc., which may be substituted by (a) C 1 -C 10, (b) oxo, (c) ) 3-thiophenaldoiminol, or (d) sulfo, or (ii) a group of the formula R 8, N-CO-R g · wherein R g 'and R g' 'are independently (a) hydrogen, (b) lower alkyl, (c) lower alkylcarbamoyl, or (d) sulfo, R 9 is 1 (i) lower alkyl which may be substituted by hydroxyl, formyloxy or halogen, (ii) phenyl, (iii) 5-membered, single sulfur, nitrogen - or an oxygen atom-containing heterocyclic group such as thienyl, furyl, pyrrolyl, etc., which may be substituted by amino, (iv) 2-propynyl or (v) benzothienyl, (C) a group of the formula R 10 -C CO-iz „N -O- R 13 wherein R 12 is (i) a 5-membered heterocyclic group containing one nitrogen, sulfur or oxygen atom, optionally further having a nitrogen atom, such as 2-thiazolyl, 4-thiazolyl 177 79528 yl, 5-thiazolyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, etc., and which may be substituted by (a) amino, (b) C2-C4 acylamino which may be substituted with halogen, or (ii) 2- (sulfoamino, formylamino, methylthioacetamido or tritylamino) thiazol-4-yl, R 13 is (i) lower alkyl or (ii) a group of the formula -R 14 -R 15, wherein R14 is lower alkylene and R15 is carboxyl, a conventional carboxylic ester such as methyl, ethyl, propyl, t-butyl, p-nitrobenzyl, 2-trimethylsilylethyl, t-butyldiphenylsilyl, diphenylmethyl ester, or a 5-membered heterocyclic group containing 3 to 4 nitrogen atoms, (D) a group of the formula R 1 -CH-CO- wherein R 17 is halogen, (E) a group of the formula r 19 -ch 2-co- wherein R19 is (i) phenyl, (ii) phenoxy or (iii) a 5- or 6-membered heterocyclic group having one sulfur atom or 2 to 4 nitrogen atoms, such as 2-thienyl, 3-thienyl , 1-tetrazolyl, 5-tetrazolyl, imidazolyl, etc .; (3) an amino group protected by an amino-protecting group 178,79528 used in the field of β-lactam and peptide syntheses; (4) 2 - ((2- (tritylamino or amino) thiazol-4-yl) carboxymethyliminooxy) -2-methylpropionamide; R 4 is (1) azido, (2) halogen, (3) an amino group which may be acylated, the acyl moiety being lower alkylcarbonyl, (4) a group of the following formulas -OR 5, -S (O) n R 5, or -SS-R 5 wherein R 5 is (A) a C 1 -C 10 hydrocarbon which may be substituted by (1) lower alkoxycarbonyl or (2) an amino which may be acylated, the acyl moiety being formyl, acetyl or p-nitrobenzyloxycarbonyl, (B) a carbonyl group substituted with C 1 -C 10 biliary hydrogen, which may be substituted with phenyl, (C) tetrazolyl, which may be substituted with lower alkyl, or (D) benzothiazolyl; and n is 0, 1 or 2; or (5) n-propylthio-thiocarbonylthio; 179 79528 or a pharmaceutically acceptable salt or ester thereof, characterized in that a) a compound X p / S 2 1 (I1) 1 of the following formula (II) wherein R 2 is an acylated or protected amino group as defined for R 1, and X and R 4 are as defined above, or a salt or silyl derivative thereof is sulfonated, followed, if necessary, by deprotection in the case where R 2 is a protected amino group as defined for R 1, or b) to prepare a compound of formula (I) wherein R 1 is an acylated amino group and X and R 4 are as defined above, a compound of the following formula (III) y R 4 is NH 2 -? / -N (III> O 2 SO 2 H) wherein X and R 4 are as defined above, or its salt or silyl derivative is acylated, and if desired, the compound thus obtained is converted into a pharmaceutically acceptable salt or ester thereof. Process according to Claim 1, characterized in that 3- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -4-methylthio-2-oxoazetidine-1-sulfonic acid or a pharmaceutically acceptable salt thereof. 180 79528 Process according to Claim 1, characterized in that 3- (2- (2-aminothiazol-4-yl) -2 - ((1-carboxy-1-methylethoxy) imino) acetamido) -4-methylthio-2- oxo-azetidine-1-sulfonic acid or a pharmaceutically acceptable salt thereof. Process according to Claim 1, characterized in that 4- (2-acetamidoethyl) thio-3- (2- (2-aminothiazol-4-yl) -2 - ((1-carboxy-1-methylethoxy) -imino) acetamido) -2-oxoazetidine-1-sulfonic acid or a pharmaceutically acceptable salt thereof. Process according to Claim 1, characterized in that 4-azido-3- (2- (2-aminothiazol-4-yl) -2 - ((1-carboxy-1-methylethoxy) imino) acetamido) is prepared. -2-oxo-azetidine-1-sulfonic acid or a pharmaceutically acceptable salt thereof. - I t 181 79528